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Liprandi ÁS, Liprandi MIS, Zaidel EJ, Aisenberg GM, Baranchuk A, Barbosa ECD, Sánchez GB, Alexander B, Zanetti FTL, Santi RL, Múnera-Echeverri AG, Perel P, Piskorz D, Ruiz-Mori CE, Saucedo J, Valdez O, Juanatey JRG, Piñeiro DJ, Pinto FJ, Quintana FSW. Influenza Vaccination for the Prevention of Cardiovascular Disease in the Americas: Consensus document of the Inter-American Society of Cardiology and the Word Heart Federation. Glob Heart 2021; 16:55. [PMID: 34381676 PMCID: PMC8344961 DOI: 10.5334/gh.1069] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 06/23/2021] [Indexed: 02/01/2023] Open
Abstract
Background Cardiovascular mortality is decreasing but remains the leading cause of death world-wide. Respiratory infections such as influenza significantly contribute to morbidity and mortality in patients with cardiovascular disease. Despite of proven benefits, influenza vaccination is not fully implemented, especially in Latin America. Objective The aim was to develop a regional consensus with recommendations regarding influenza vaccination and cardiovascular disease. Methods A multidisciplinary team composed by experts in the management and prevention of cardiovascular disease from the Americas, convened by the Inter-American Society of Cardiology (IASC) and the World Heart Federation (WHF), participated in the process and the formulation of statements. The modified RAND/UCLA methodology was used. This document was supported by a grant from the WHF. Results An extensive literature search was divided into seven questions, and a total of 23 conclusions and 29 recommendations were achieved. There was no disagreement among experts in the conclusions or recommendations. Conclusions There is a strong correlation between influenza and cardiovascular events. Influenza vaccination is not only safe and a proven strategy to reduce cardiovascular events, but it is also cost saving. We found several barriers for its global implementation and potential strategies to overcome them.
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Affiliation(s)
- Álvaro Sosa Liprandi
- School of Medicine, University of Buenos Aires, AR
- Cardiology Department, Sanatorio Güemes, Buenos Aires, AR
- InterAmerican Society of Cardiology, AR
| | | | - Ezequiel José Zaidel
- Cardiology Department, Sanatorio Güemes, Buenos Aires, AR
- Pharmacology Department, School of Medicine, University of Buenos Aires, AR
| | - Gabriel M. Aisenberg
- University of Texas John P and Kathrine G McGovern School of Medicine, Houston, Texas, US
| | - Adrián Baranchuk
- Division of Cardiology, Kingston Health Science Center, Queen’s University, Kingston, Ontario, CA
| | - Eduardo Costa Duarte Barbosa
- Cardiology Department, Hospital Sao Francisco-Santa Casa, Porto Alegre, BR
- Artery LatAm, LatinAmerican Society of Hypertension, BR
| | - Gabriela Borrayo Sánchez
- Cardiology Department, Mexican Social Security Institute, Mexican National Association of Cardiologists, MX
| | - Bryce Alexander
- Division of Cardiology, Kingston Health Science Center, Queen’s University, Kingston, Ontario, CA
| | | | - Ricardo López Santi
- Cardiology Department, Hospital Italiano de La Plata, Buenos Aires, AR
- Argentine Federation of Cardiology, AR
| | | | - Pablo Perel
- Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, GB
- World Heart Federation, Geneva, CH
| | - Daniel Piskorz
- Argentine Federation of Cardiology, AR
- Cardiology Department, British Hospital of Rosario, Santa Fe, AR
| | | | - Jorge Saucedo
- Cardiology Department, Froedtert Hospital and Medical College, Milwaukee, US
| | - Osiris Valdez
- Cardiology Department, Centro Médico Central Romana, La Romana, DO
- Central America Society of Hypertension, DO
| | - José Ramón González Juanatey
- Cardiology Department, Hospital Clínico Universitario de Santiago de Compostela, Spanish Society of Cardiology, ES
| | | | - Fausto J. Pinto
- World Heart Federation, Geneva, CH
- Cardiology Department, Hospital Santa María, PT
- University of Lisbon, PT
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Khalaj‐Hedayati A, Chua CLL, Smooker P, Lee KW. Nanoparticles in influenza subunit vaccine development: Immunogenicity enhancement. Influenza Other Respir Viruses 2020; 14:92-101. [PMID: 31774251 PMCID: PMC6928032 DOI: 10.1111/irv.12697] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 09/14/2019] [Accepted: 10/01/2019] [Indexed: 12/25/2022] Open
Abstract
The threat of novel influenza infections has sparked research efforts to develop subunit vaccines that can induce a more broadly protective immunity by targeting selected regions of the virus. In general, subunit vaccines are safer but may be less immunogenic than whole cell inactivated or live attenuated vaccines. Hence, novel adjuvants that boost immunogenicity are increasingly needed as we move toward the era of modern vaccines. In addition, targeting, delivery, and display of the selected antigens on the surface of professional antigen-presenting cells are also important in vaccine design and development. The use of nanosized particles can be one of the strategies to enhance immunogenicity as they can be efficiently recognized by antigen-presenting cells. They can act as both immunopotentiators and delivery system for the selected antigens. This review will discuss on the applications, advantages, limitations, and types of nanoparticles (NPs) used in the preparation of influenza subunit vaccine candidates to enhance humoral and cellular immune responses.
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Affiliation(s)
- Atin Khalaj‐Hedayati
- School of BiosciencesFaculty of Health and Medical SciencesTaylor's UniversitySubang JayaMalaysia
| | - Caroline Lin Lin Chua
- School of BiosciencesFaculty of Health and Medical SciencesTaylor's UniversitySubang JayaMalaysia
| | - Peter Smooker
- Department of Biosciences and Food TechnologySchool of ScienceRMIT UniversityBundooraVictoriaAustralia
| | - Khai Wooi Lee
- School of BiosciencesFaculty of Health and Medical SciencesTaylor's UniversitySubang JayaMalaysia
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Yakuboğulları N, Genç R, Çöven F, Nalbantsoy A, Bedir E. Development of adjuvant nanocarrier systems for seasonal influenza A (H3N2) vaccine based on Astragaloside VII and gum tragacanth (APS). Vaccine 2019; 37:3638-3645. [PMID: 31155418 DOI: 10.1016/j.vaccine.2019.05.038] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 04/25/2019] [Accepted: 05/13/2019] [Indexed: 01/21/2023]
Abstract
Adjuvants are chemical/biological substances that are used in vaccines to increase the immunogenicity of antigens. A few adjuvants have been developed for use in human vaccines because of their limitations including lack of efficacy, unacceptable local or systemic toxicity, the difficulty of manufacturing, poor stability, and high cost. For that reasons, novel adjuvants/adjuvant systems are under search. Astragaloside VII (AST-VII), isolated from Astragalus trojanus, exhibited significant cellular and humoral immune responses. The polysaccharides (APS) obtained from the roots of Astragalus species have been used in traditional Chinese medicine and possess strong immunomodulatory properties. In the present study, the immunomodulatory effects of a newly developed nanocarrier system (APNS: APS containing carrier) and its AST-VII containing formulation (ANS: AST-VII + APNS), on seasonal influenza A (H3N2) vaccine were investigated. Inactivated H3N2 alone or its combinations with test compounds/formulations were intramuscularly injected into Swiss albino mice. Four weeks after immunization, the immune responses were evaluated in terms of antibody and cytokine responses as well as splenocyte proliferation. APNS demonstrated Th2 mediated response by increasing IgG1 antibody titers, whereas ANS showed response towards Th1/Th2 balance and Th17 by producing of IFN-γ, IL-17A and IgG2a. Based on these results, we propose that APNS and ANS are good candidates to be utilized in seasonal influenza A vaccines as adjuvants/carrier systems.
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Affiliation(s)
- Nilgün Yakuboğulları
- Izmir Institute of Technology, Faculty of Engineering, Department of Bioengineering, 35433 Gülbahçe, Urla, Izmir, Turkey
| | - Rükan Genç
- Mersin University, Faculty of Engineering, Department of Chemical Engineering, 33343 Mersin, Turkey
| | - Fethiye Çöven
- Bornova Veterinary Control and Research Institute, 35100 Bornova, Izmir, Turkey
| | - Ayşe Nalbantsoy
- Ege University, Faculty of Engineering, Department of Bioengineering, 35100 Bornova, Izmir, Turkey.
| | - Erdal Bedir
- Izmir Institute of Technology, Faculty of Engineering, Department of Bioengineering, 35433 Gülbahçe, Urla, Izmir, Turkey.
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Variation at Extra-epitopic Amino Acid Residues Influences Suppression of Influenza Virus Replication by M1 58-66 Epitope-Specific CD8 + T Lymphocytes. J Virol 2018; 92:JVI.00232-18. [PMID: 29593036 DOI: 10.1128/jvi.00232-18] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 03/19/2018] [Indexed: 01/05/2023] Open
Abstract
Influenza virus-specific CD8+ T lymphocytes (CTLs) contribute to clearance of influenza virus infections and reduce disease severity. Variation at amino acid residues located in or outside CTL epitopes has been shown to affect viral recognition by virus-specific CTLs. In the present study, we investigated the effect of naturally occurring variation at residues outside the conserved immunodominant and HLA*0201-restricted M158-66 epitope, located in the influenza virus M1 protein, on the extent of virus replication in the presence of CTLs specific for the epitope. To this end, we used isogenic viruses with an M1 gene segment derived from either an avian or a human influenza virus, HLA-transgenic human epithelial cells, human T cell clones specific for the M158-66 epitope or a control epitope, and a novel, purposely developed in vitro system to coculture influenza virus-infected cells with T cells. We found that the M gene segment of a human influenza A/H3N2 virus afforded the virus the capacity to replicate better in the presence of M158-66-specific CTLs than the M gene segment of avian viruses. These findings are in concordance with previously observed differential CTL activation, caused by variation at extra-epitopic residues, and may reflect an immune adaptation strategy of human influenza viruses that allows them to cope with potent CTL immunity to the M158-66 epitope in HLA-A*0201-positive individuals, resulting in increased virus replication and shedding and possibly increasing disease severity.IMPORTANCE Influenza viruses are among the leading causes of acute respiratory tract infections. CD8+ T lymphocytes display a high degree of cross-reactivity with influenza A viruses of various subtypes and are considered an important correlate of protection. Unraveling viral immune evasion strategies and identifying signs of immune adaptation are important for defining the role of CD8+ T lymphocytes in affording protection more accurately. Improving our insight into the interaction between influenza viruses and virus-specific CD8+ T lymphocyte immunity may help to advance our understanding of influenza virus epidemiology, aid in risk assessment of potentially pandemic influenza virus strains, and benefit the design of vaccines that induce more broadly protective immunity.
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Saletti G, Gerlach T, Rimmelzwaan GF. Influenza vaccines: 'tailor-made' or 'one fits all'. Curr Opin Immunol 2018; 53:102-110. [PMID: 29734023 DOI: 10.1016/j.coi.2018.04.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 04/12/2018] [Accepted: 04/16/2018] [Indexed: 02/02/2023]
Abstract
Currently used inactivated influenza vaccines aim at the induction of virus-neutralizing antibodies directed to the variable head domain of the viral hemagglutinin. Although these vaccines are effective against antigenically matching virus strains, they offer little protection against antigenically distinct drift variants or potentially pandemic viruses of alternative subtypes. In the last decades, the threat of novel influenza pandemics has sparked research efforts to develop vaccines that induce more broadly protective immunity. Here, we discuss the immune responses induced by conventional 'tailor-made' inactivated and live influenza vaccines and novel 'one fits all' candidate vaccines able to induce cross-reactive virus-specific antibody and T cell responses and to afford protection to a wider range of influenza viruses.
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Affiliation(s)
- Giulietta Saletti
- University of Veterinary Medicine (TiHo), Research Center for Emerging Infections and Zoonoses (RIZ), Bünteweg 17, 30559 Hannover, Germany
| | - Thomas Gerlach
- University of Veterinary Medicine (TiHo), Research Center for Emerging Infections and Zoonoses (RIZ), Bünteweg 17, 30559 Hannover, Germany
| | - Guus F Rimmelzwaan
- University of Veterinary Medicine (TiHo), Research Center for Emerging Infections and Zoonoses (RIZ), Bünteweg 17, 30559 Hannover, Germany.
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Jefferson T, Rivetti A, Di Pietrantonj C, Demicheli V, Cochrane Acute Respiratory Infections Group. Vaccines for preventing influenza in healthy children. Cochrane Database Syst Rev 2018; 2:CD004879. [PMID: 29388195 PMCID: PMC6491174 DOI: 10.1002/14651858.cd004879.pub5] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
BACKGROUND The consequences of influenza in children and adults are mainly absenteeism from school and work. However, the risk of complications is greatest in children and people over 65 years of age. This is an update of a review published in 2011. Future updates of this review will be made only when new trials or vaccines become available. Observational data included in previous versions of the review have been retained for historical reasons but have not been updated because of their lack of influence on the review conclusions. OBJECTIVES To assess the effects (efficacy, effectiveness, and harm) of vaccines against influenza in healthy children. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 12), which includes the Cochrane Acute Respiratory Infections Group Specialised Register, MEDLINE (1966 to 31 December 2016), Embase (1974 to 31 December 2016), WHO International Clinical Trials Registry Platform (ICTRP; 1 July 2017), and ClinicalTrials.gov (1 July 2017). SELECTION CRITERIA Randomised controlled trials comparing influenza vaccines with placebo or no intervention in naturally occurring influenza in healthy children under 16 years. Previous versions of this review included 19 cohort and 11 case-control studies. We are no longer updating the searches for these study designs but have retained the observational studies for historical purposes. DATA COLLECTION AND ANALYSIS Review authors independently assessed risk of bias and extracted data. We used GRADE to rate the certainty of evidence for the key outcomes of influenza, influenza-like illness (ILI), complications (hospitalisation, ear infection), and adverse events. Due to variation in control group risks for influenza and ILI, absolute effects are reported as the median control group risk, and numbers needed to vaccinate (NNVs) are reported accordingly. For other outcomes aggregate control group risks are used. MAIN RESULTS We included 41 clinical trials (> 200,000 children). Most of the studies were conducted in children over the age of two and compared live attenuated or inactivated vaccines with placebo or no vaccine. Studies were conducted over single influenza seasons in the USA, Western Europe, Russia, and Bangladesh between 1984 and 2013. Restricting analyses to studies at low risk of bias showed that influenza and otitis media were the only outcomes where the impact of bias was negligible. Variability in study design and reporting impeded meta-analysis of harms outcomes.Live attenuated vaccinesCompared with placebo or do nothing, live attenuated influenza vaccines probably reduce the risk of influenza infection in children aged 3 to 16 years from 18% to 4% (risk ratio (RR) 0.22, 95% confidence interval (CI) 0.11 to 0.41; 7718 children; moderate-certainty evidence), and they may reduce ILI by a smaller degree, from 17% to 12% (RR 0.69, 95% CI 0.60 to 0.80; 124,606 children; low-certainty evidence). Seven children would need to be vaccinated to prevent one case of influenza, and 20 children would need to be vaccinated to prevent one child experiencing an ILI. Acute otitis media is probably similar following vaccine or placebo during seasonal influenza, but this result comes from a single study with particularly high rates of acute otitis media (RR 0.98, 95% CI 0.95 to 1.01; moderate-certainty evidence). There was insufficient information available to determine the effect of vaccines on school absenteeism due to very low-certainty evidence from one study. Vaccinating children may lead to fewer parents taking time off work, although the CI includes no effect (RR 0.69, 95% CI 0.46 to 1.03; low-certainty evidence). Data on the most serious consequences of influenza complications leading to hospitalisation were not available. Data from four studies measuring fever following vaccination varied considerably, from 0.16% to 15% in children who had live vaccines, while in the placebo groups the proportions ranged from 0.71% to 22% (very low-certainty evidence). Data on nausea were not reported.Inactivated vaccinesCompared with placebo or no vaccination, inactivated vaccines reduce the risk of influenza in children aged 2 to 16 years from 30% to 11% (RR 0.36, 95% CI 0.28 to 0.48; 1628 children; high-certainty evidence), and they probably reduce ILI from 28% to 20% (RR 0.72, 95% CI 0.65 to 0.79; 19,044 children; moderate-certainty evidence). Five children would need to be vaccinated to prevent one case of influenza, and 12 children would need to be vaccinated to avoid one case of ILI. The risk of otitis media is probably similar between vaccinated children and unvaccinated children (31% versus 27%), although the CI does not exclude a meaningful increase in otitis media following vaccination (RR 1.15, 95% CI 0.95 to 1.40; 884 participants; moderate-certainty evidence). There was insufficient information available to determine the effect of vaccines on school absenteeism due to very low-certainty evidence from one study. We identified no data on parental working time lost, hospitalisation, fever, or nausea.We found limited evidence on secondary cases, requirement for treatment of lower respiratory tract disease, and drug prescriptions. One brand of monovalent pandemic vaccine was associated with a sudden loss of muscle tone triggered by the experience of an intense emotion (cataplexy) and a sleep disorder (narcolepsy) in children. Evidence of serious harms (such as febrile fits) was sparse. AUTHORS' CONCLUSIONS In children aged between 3 and 16 years, live influenza vaccines probably reduce influenza (moderate-certainty evidence) and may reduce ILI (low-certainty evidence) over a single influenza season. In this population inactivated vaccines also reduce influenza (high-certainty evidence) and may reduce ILI (low-certainty evidence). For both vaccine types, the absolute reduction in influenza and ILI varied considerably across the study populations, making it difficult to predict how these findings translate to different settings. We found very few randomised controlled trials in children under two years of age. Adverse event data were not well described in the available studies. Standardised approaches to the definition, ascertainment, and reporting of adverse events are needed. Identification of all global cases of potential harms is beyond the scope of this review.
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Affiliation(s)
- Tom Jefferson
- University of OxfordCentre for Evidence Based MedicineOxfordUKOX2 6GG
| | - Alessandro Rivetti
- ASL CN2 Alba BraDipartimento di Prevenzione ‐ S.Pre.S.A.LVia Vida 10AlbaPiemonteItaly12051
| | - Carlo Di Pietrantonj
- Local Health Unit Alessandria‐ ASL ALRegional Epidemiology Unit SeREMIVia Venezia 6AlessandriaAlessandriaItaly15121
| | - Vittorio Demicheli
- Azienda Sanitaria Locale ASL ALServizio Regionale di Riferimento per l'Epidemiologia, SSEpi‐SeREMIVia Venezia 6AlessandriaPiemonteItaly15121
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Demicheli V, Jefferson T, Ferroni E, Rivetti A, Di Pietrantonj C, Cochrane Acute Respiratory Infections Group. Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev 2018; 2:CD001269. [PMID: 29388196 PMCID: PMC6491184 DOI: 10.1002/14651858.cd001269.pub6] [Citation(s) in RCA: 131] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND The consequences of influenza in adults are mainly time off work. Vaccination of pregnant women is recommended internationally. This is an update of a review published in 2014. Future updates of this review will be made only when new trials or vaccines become available. Observational data included in previous versions of the review have been retained for historical reasons but have not been updated due to their lack of influence on the review conclusions. OBJECTIVES To assess the effects (efficacy, effectiveness, and harm) of vaccines against influenza in healthy adults, including pregnant women. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 12), MEDLINE (January 1966 to 31 December 2016), Embase (1990 to 31 December 2016), the WHO International Clinical Trials Registry Platform (ICTRP; 1 July 2017), and ClinicalTrials.gov (1 July 2017), as well as checking the bibliographies of retrieved articles. SELECTION CRITERIA Randomised controlled trials (RCTs) or quasi-RCTs comparing influenza vaccines with placebo or no intervention in naturally occurring influenza in healthy individuals aged 16 to 65 years. Previous versions of this review included observational comparative studies assessing serious and rare harms cohort and case-control studies. Due to the uncertain quality of observational (i.e. non-randomised) studies and their lack of influence on the review conclusions, we decided to update only randomised evidence. The searches for observational comparative studies are no longer updated. DATA COLLECTION AND ANALYSIS Two review authors independently assessed trial quality and extracted data. We rated certainty of evidence for key outcomes (influenza, influenza-like illness (ILI), hospitalisation, and adverse effects) using GRADE. MAIN RESULTS We included 52 clinical trials of over 80,000 people assessing the safety and effectiveness of influenza vaccines. We have presented findings from 25 studies comparing inactivated parenteral influenza vaccine against placebo or do-nothing control groups as the most relevant to decision-making. The studies were conducted over single influenza seasons in North America, South America, and Europe between 1969 and 2009. We did not consider studies at high risk of bias to influence the results of our outcomes except for hospitalisation.Inactivated influenza vaccines probably reduce influenza in healthy adults from 2.3% without vaccination to 0.9% (risk ratio (RR) 0.41, 95% confidence interval (CI) 0.36 to 0.47; 71,221 participants; moderate-certainty evidence), and they probably reduce ILI from 21.5% to 18.1% (RR 0.84, 95% CI 0.75 to 0.95; 25,795 participants; moderate-certainty evidence; 71 healthy adults need to be vaccinated to prevent one of them experiencing influenza, and 29 healthy adults need to be vaccinated to prevent one of them experiencing an ILI). The difference between the two number needed to vaccinate (NNV) values depends on the different incidence of ILI and confirmed influenza among the study populations. Vaccination may lead to a small reduction in the risk of hospitalisation in healthy adults, from 14.7% to 14.1%, but the CI is wide and does not rule out a large benefit (RR 0.96, 95% CI 0.85 to 1.08; 11,924 participants; low-certainty evidence). Vaccines may lead to little or no small reduction in days off work (-0.04 days, 95% CI -0.14 days to 0.06; low-certainty evidence). Inactivated vaccines cause an increase in fever from 1.5% to 2.3%.We identified one RCT and one controlled clinical trial assessing the effects of vaccination in pregnant women. The efficacy of inactivated vaccine containing pH1N1 against influenza was 50% (95% CI 14% to 71%) in mothers (NNV 55), and 49% (95% CI 12% to 70%) in infants up to 24 weeks (NNV 56). No data were available on efficacy against seasonal influenza during pregnancy. Evidence from observational studies showed effectiveness of influenza vaccines against ILI in pregnant women to be 24% (95% CI 11% to 36%, NNV 94), and against influenza in newborns from vaccinated women to be 41% (95% CI 6% to 63%, NNV 27).Live aerosol vaccines have an overall effectiveness corresponding to an NNV of 46. The performance of one- or two-dose whole-virion 1968 to 1969 pandemic vaccines was higher (NNV 16) against ILI and (NNV 35) against influenza. There was limited impact on hospitalisations in the 1968 to 1969 pandemic (NNV 94). The administration of both seasonal and 2009 pandemic vaccines during pregnancy had no significant effect on abortion or neonatal death, but this was based on observational data sets. AUTHORS' CONCLUSIONS Healthy adults who receive inactivated parenteral influenza vaccine rather than no vaccine probably experience less influenza, from just over 2% to just under 1% (moderate-certainty evidence). They also probably experience less ILI following vaccination, but the degree of benefit when expressed in absolute terms varied across different settings. Variation in protection against ILI may be due in part to inconsistent symptom classification. Certainty of evidence for the small reductions in hospitalisations and time off work is low. Protection against influenza and ILI in mothers and newborns was smaller than the effects seen in other populations considered in this review.Vaccines increase the risk of a number of adverse events, including a small increase in fever, but rates of nausea and vomiting are uncertain. The protective effect of vaccination in pregnant women and newborns is also very modest. We did not find any evidence of an association between influenza vaccination and serious adverse events in the comparative studies considered in this review. Fifteen included RCTs were industry funded (29%).
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Affiliation(s)
- Vittorio Demicheli
- Azienda Sanitaria Locale ASL ALServizio Regionale di Riferimento per l'Epidemiologia, SSEpi‐SeREMIVia Venezia 6AlessandriaPiemonteItaly15121
| | - Tom Jefferson
- University of OxfordCentre for Evidence Based MedicineOxfordUKOX2 6GG
| | - Eliana Ferroni
- Regional Center for Epidemiology, Veneto RegionEpidemiological System of the Veneto RegionPassaggio Gaudenzio 1PadovaItaly35131
| | - Alessandro Rivetti
- ASL CN2 Alba BraDipartimento di Prevenzione ‐ S.Pre.S.A.LVia Vida 10AlbaPiemonteItaly12051
| | - Carlo Di Pietrantonj
- Local Health Unit Alessandria‐ ASL ALRegional Epidemiology Unit SeREMIVia Venezia 6AlessandriaAlessandriaItaly15121
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Abstract
In spite of current influenza vaccines being immunogenic, evolution of the influenza virus can reduce efficacy and so influenza remains a major threat to public health. One approach to improve influenza vaccines is to include adjuvants; substances that boost the immune response. Adjuvants are particularly beneficial for influenza vaccines administered during a pandemic when a rapid response is required or for use in patients with impaired immune responses, such as infants and the elderly. This review outlines the current use of adjuvants in human influenza vaccines, including what they are, why they are used and what is known of their mechanism of action. To date, six adjuvants have been used in licensed human vaccines: Alum, MF59, AS03, AF03, virosomes and heat labile enterotoxin (LT). In general these adjuvants are safe and well tolerated, but there have been some rare adverse events when adjuvanted vaccines are used at a population level that may discourage the inclusion of adjuvants in influenza vaccines, for example the association of LT with Bell's Palsy. Improved understanding about the mechanisms of the immune response to vaccination and infection has led to advances in adjuvant technology and we describe the experimental adjuvants that have been tested in clinical trials for influenza but have not yet progressed to licensure. Adjuvants alone are not sufficient to improve influenza vaccine efficacy because they do not address the underlying problem of mismatches between circulating virus and the vaccine. However, they may contribute to improved efficacy of next-generation influenza vaccines and will most likely play a role in the development of effective universal influenza vaccines, though what that role will be remains to be seen.
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Affiliation(s)
- John S Tregoning
- a Mucosal Infection and Immunity group, Section of Virology, Department of Medicine , St Mary's Campus, Imperial College London , UK
| | - Ryan F Russell
- a Mucosal Infection and Immunity group, Section of Virology, Department of Medicine , St Mary's Campus, Imperial College London , UK
| | - Ekaterina Kinnear
- a Mucosal Infection and Immunity group, Section of Virology, Department of Medicine , St Mary's Campus, Imperial College London , UK
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Vemula SV, Sayedahmed EE, Sambhara S, Mittal SK. Vaccine approaches conferring cross-protection against influenza viruses. Expert Rev Vaccines 2017; 16:1141-1154. [PMID: 28925296 DOI: 10.1080/14760584.2017.1379396] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Annual vaccination is one of the most efficient and cost-effective strategies to prevent and control influenza epidemics. Most of the currently available influenza vaccines are strong inducers of antibody responses against viral surface proteins, hemagglutinin (HA) and neuraminidase (NA), but are poor inducers of cell-mediated immune responses against conserved internal proteins. Moreover, due to the high variability of viral surface proteins because of antigenic drift or antigenic shift, many of the currently licensed vaccines confer little or no protection against drift or shift variants. Areas covered: Next generation influenza vaccines that can induce humoral immune responses to receptor-binding epitopes as well as broadly neutralizing conserved epitopes, and cell-mediated immune responses against highly conserved internal proteins would be effective against variant viruses as well as a novel pandemic influenza until circulating strain-specific vaccines become available. Here we discuss vaccine approaches that have the potential to provide broad spectrum protection against influenza viruses. Expert commentary: Based on current progress in defining cross-protective influenza immunity, it seems that the development of a universal influenza vaccine is feasible. It would revolutionize the strategy for influenza pandemic preparedness, and significantly impact the shelf-life and protection efficacy of seasonal influenza vaccines.
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Affiliation(s)
- Sai V Vemula
- a Department of Comparative Pathobiology and Purdue Institute for Immunology , Inflammation and Infectious Disease, Purdue University , West Lafayette , IN , USA
| | - Ekramy E Sayedahmed
- a Department of Comparative Pathobiology and Purdue Institute for Immunology , Inflammation and Infectious Disease, Purdue University , West Lafayette , IN , USA
| | - Suryaprakash Sambhara
- b Influenza Division , Centers for Disease Control and Prevention , Atlanta , GA , USA
| | - Suresh K Mittal
- a Department of Comparative Pathobiology and Purdue Institute for Immunology , Inflammation and Infectious Disease, Purdue University , West Lafayette , IN , USA
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Increased Protein Degradation Improves Influenza Virus Nucleoprotein-Specific CD8+ T Cell Activation In Vitro but Not in C57BL/6 Mice. J Virol 2016; 90:10209-10219. [PMID: 27581985 DOI: 10.1128/jvi.01633-16] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Accepted: 08/25/2016] [Indexed: 11/20/2022] Open
Abstract
Due to antigenic drift of influenza viruses, seasonal influenza vaccines need to be updated annually. These vaccines are based on predictions of strains likely to circulate in the next season. However, vaccine efficacy is greatly reduced in the case of a mismatch between circulating and vaccine strains. Furthermore, novel antigenically distinct influenza viruses are introduced into the human population from animal reservoirs occasionally and may cause pandemic outbreaks. To dampen the impact of seasonal and pandemic influenza, vaccines that induce broadly protective and long-lasting immunity are preferred. Because influenza virus-specific CD8+ T cells are directed mainly against relatively conserved internal proteins, like nucleoprotein (NP), they are highly cross-reactive and afford protection against infection with antigenically distinct influenza virus strains, so-called heterosubtypic immunity. Here, we used modified vaccinia virus Ankara (MVA) as a vaccine vector for the induction of influenza virus NP-specific CD8+ T cells. To optimize the induction of CD8+ T cell responses, we made several modifications to NP, aiming at retaining the protein in the cytosol or targeting it to the proteasome. We hypothesized that these strategies would increase antigen processing and presentation and thus improve the induction of CD8+ T cell responses. We showed that NP with increased degradation rates improved CD8+ T cell activation in vitro if the amount of antigen was limited or if CD8+ T cells were of low functional avidity. However, after immunization of C57BL/6 mice, no differences were detected between modified NP and wild-type NP (NPwt), since NPwt already induced optimal CD8+ T cell responses. IMPORTANCE Due to the continuous antigenic drift of seasonal influenza viruses and the threat of a novel pandemic, there is a great need for the development of novel influenza vaccines that offer broadly protective immunity against multiple subtypes. CD8+ T cells can provide immunity against multiple subtypes of influenza viruses by the recognition of relatively conserved internal antigens. In this study, we aimed at optimizing the CD8+ T cell response to influenza A virus by making modifications to influenza A virus nucleoprotein (NP) expressed from the modified vaccinia virus Ankara (MVA) vaccine vector. These modifications resulted in increased antigen degradation, thereby producing elevated levels of peptides that can be presented on major histocompatibility complex (MHC) class I molecules to CD8+ T cells. Although we were unable to increase the NP-specific immune response in the mouse strain used, this approach may have benefits for vaccine development using less-immunogenic proteins.
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Bobbala S, Hook S. Is There an Optimal Formulation and Delivery Strategy for Subunit Vaccines? Pharm Res 2016; 33:2078-97. [DOI: 10.1007/s11095-016-1979-0] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 06/21/2016] [Indexed: 12/16/2022]
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Gianchecchi E, Trombetta C, Piccirella S, Montomoli E. Evaluating influenza vaccines: progress and perspectives. Future Virol 2016. [DOI: 10.2217/fvl-2016-0012] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Severe influenza infections are responsible for 3–5 million cases worldwide and 250,000–500,000 deaths per year. Although vaccination is the primary and most effective means of inducing protection against influenza viruses, it also presents limitations. This review outlines the promising steps that have been taken toward the development of a broadly protective influenza virus vaccine through the use of new technologies. The future challenge is to develop a broadly protective vaccine that is able to induce long-term protection against antigenically variant influenza viruses, regardless of antigenic shift and drift, and thus to protect against seasonal and pandemic influenza viruses.
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Affiliation(s)
- Elena Gianchecchi
- VisMederi Srl, Enterprise of Service in Life Sciences, Via Fiorentina 1, 53100 Siena, Italy
| | - Claudia Trombetta
- Department of Molecular & Developmental Medicine, University of Siena, Via Aldo Moro, 53100 Siena, Italy
| | - Simona Piccirella
- VisMederi Srl, Enterprise of Service in Life Sciences, Via Fiorentina 1, 53100 Siena, Italy
| | - Emanuele Montomoli
- VisMederi Srl, Enterprise of Service in Life Sciences, Via Fiorentina 1, 53100 Siena, Italy
- Department of Molecular & Developmental Medicine, University of Siena, Via Aldo Moro, 53100 Siena, Italy
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13
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Differential Recognition of Influenza A Viruses by M158-66 Epitope-Specific CD8+ T Cells Is Determined by Extraepitopic Amino Acid Residues. J Virol 2015; 90:1009-22. [PMID: 26537686 DOI: 10.1128/jvi.02439-15] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 10/29/2015] [Indexed: 12/13/2022] Open
Abstract
UNLABELLED Natural influenza A virus infections elicit both virus-specific antibody and CD4(+) and CD8(+) T cell responses. Influenza A virus-specific CD8(+) cytotoxic T lymphocytes (CTLs) contribute to clearance of influenza virus infections. Viral CTL epitopes can display variation, allowing influenza A viruses to evade recognition by epitope-specific CTLs. Due to functional constraints, some epitopes, like the immunodominant HLA-A*0201-restricted matrix protein 1 (M158-66) epitope, are highly conserved between influenza A viruses regardless of their subtype or host species of origin. We hypothesized that human influenza A viruses evade recognition of this epitope by impairing antigen processing and presentation by extraepitopic amino acid substitutions. Activation of specific T cells was used as an indication of antigen presentation. Here, we show that the M158-66 epitope in the M1 protein derived from human influenza A virus was poorly recognized compared to the M1 protein derived from avian influenza A virus. Furthermore, we demonstrate that naturally occurring variations at extraepitopic amino acid residues affect CD8(+) T cell recognition of the M158-66 epitope. These data indicate that human influenza A viruses can impair recognition by M158-66-specific CTLs while retaining the conserved amino acid sequence of the epitope, which may represent a yet-unknown immune evasion strategy for influenza A viruses. This difference in recognition may have implications for the viral replication kinetics in HLA-A*0201 individuals and spread of influenza A viruses in the human population. The findings may aid the rational design of universal influenza vaccines that aim at the induction of cross-reactive virus-specific CTL responses. IMPORTANCE Influenza viruses are an important cause of acute respiratory tract infections. Natural influenza A virus infections elicit both humoral and cellular immunity. CD8(+) cytotoxic T lymphocytes (CTLs) are directed predominantly against conserved internal proteins and confer cross-protection, even against influenza A viruses of various subtypes. In some CTL epitopes, mutations occur that allow influenza A viruses to evade recognition by CTLs. However, the immunodominant HLA-A*0201-restricted M158-66 epitope does not tolerate mutations without loss of viral fitness. Here, we describe naturally occurring variations in amino acid residues outside the M158-66 epitope that influence the recognition of the epitope. These results provide novel insights into the epidemiology of influenza A viruses and their pathogenicity and may aid rational design of vaccines that aim at the induction of CTL responses.
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14
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Soema PC, Kompier R, Amorij JP, Kersten GFA. Current and next generation influenza vaccines: Formulation and production strategies. Eur J Pharm Biopharm 2015; 94:251-63. [PMID: 26047796 DOI: 10.1016/j.ejpb.2015.05.023] [Citation(s) in RCA: 211] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 05/27/2015] [Accepted: 05/28/2015] [Indexed: 10/23/2022]
Abstract
Vaccination is the most effective method to prevent influenza infection. However, current influenza vaccines have several limitations. Relatively long production times, limited vaccine capacity, moderate efficacy in certain populations and lack of cross-reactivity are important issues that need to be addressed. We give an overview of the current status and novel developments in the landscape of influenza vaccines from an interdisciplinary point of view. The feasibility of novel vaccine concepts not only depends on immunological or clinical outcomes, but also depends on biotechnological aspects, such as formulation and production methods, which are frequently overlooked. Furthermore, the next generation of influenza vaccines is addressed, which hopefully will bring cross-reactive influenza vaccines. These developments indicate that an exciting future lies ahead in the influenza vaccine field.
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Affiliation(s)
- Peter C Soema
- Intravacc (Institute for Translational Vaccinology), Bilthoven, The Netherlands; Division of Drug Delivery and Technology, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands
| | - Ronald Kompier
- Intravacc (Institute for Translational Vaccinology), Bilthoven, The Netherlands; FluConsult, Noordwijk, The Netherlands
| | - Jean-Pierre Amorij
- Intravacc (Institute for Translational Vaccinology), Bilthoven, The Netherlands.
| | - Gideon F A Kersten
- Intravacc (Institute for Translational Vaccinology), Bilthoven, The Netherlands; Division of Drug Delivery and Technology, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands
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15
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van de Sandt CE, Dou Y, Vogelzang-van Trierum SE, Westgeest KB, Pronk MR, Osterhaus ADME, Fouchier RAM, Rimmelzwaan GF, Hillaire MLB. Influenza B virus-specific CD8+ T-lymphocytes strongly cross-react with viruses of the opposing influenza B lineage. J Gen Virol 2015; 96:2061-2073. [PMID: 25900135 DOI: 10.1099/vir.0.000156] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Influenza B viruses fall in two antigenically distinct lineages (B/Victoria/2/1987 and B/Yamagata/16/1988 lineage) that co-circulate with influenza A viruses of the H3N2 and H1N1 subtypes during seasonal epidemics. Infections with influenza B viruses contribute considerably to morbidity and mortality in the human population. Influenza B virus neutralizing antibodies, elicited by natural infections or vaccination, poorly cross-react with viruses of the opposing influenza B lineage. Therefore, there is an increased interest in identifying other correlates of protection which could aid the development of broadly protective vaccines. blast analysis revealed high sequence identity of all viral proteins. With two online epitope prediction algorithms, putative conserved epitopes relevant for study subjects used in the present study were predicted. The cross-reactivity of influenza B virus-specific polyclonal CD8+ cytotoxic T-lymphocyte (CTL) populations obtained from HLA-typed healthy study subjects, with intra-lineage drift variants and viruses of the opposing lineage, was determined by assessing their in vitro IFN-γ response and lytic activity. Here, we show for the first time, to the best of our knowledge, that CTLs directed to viruses of the B/Victoria/2/1987 lineage cross-react with viruses of the B/Yamagata/16/1988 lineage and vice versa.
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Affiliation(s)
| | - YingYing Dou
- Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands
| | | | - Kim B Westgeest
- Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands
| | - Mark R Pronk
- Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands
| | - Albert D M E Osterhaus
- Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.,ViroClinics Biosciences BV, Rotterdam, The Netherlands
| | - Ron A M Fouchier
- Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands
| | - Guus F Rimmelzwaan
- ViroClinics Biosciences BV, Rotterdam, The Netherlands.,Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands
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16
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Developing Universal Influenza Vaccines: Hitting the Nail, Not Just on the Head. Vaccines (Basel) 2015; 3:239-62. [PMID: 26343187 PMCID: PMC4494343 DOI: 10.3390/vaccines3020239] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Revised: 03/11/2015] [Accepted: 03/17/2015] [Indexed: 12/29/2022] Open
Abstract
Influenza viruses have a huge impact on public health. Current influenza vaccines need to be updated annually and protect poorly against antigenic drift variants or novel emerging subtypes. Vaccination against influenza can be improved in two important ways, either by inducing more broadly protective immune responses or by decreasing the time of vaccine production, which is relevant especially during a pandemic outbreak. In this review, we outline the current efforts to develop so-called “universal influenza vaccines”, describing antigens that may induce broadly protective immunity and novel vaccine production platforms that facilitate timely availability of vaccines.
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Trombetta CM, Perini D, Mather S, Temperton N, Montomoli E. Overview of Serological Techniques for Influenza Vaccine Evaluation: Past, Present and Future. Vaccines (Basel) 2014; 2:707-34. [PMID: 26344888 PMCID: PMC4494249 DOI: 10.3390/vaccines2040707] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Revised: 07/25/2014] [Accepted: 09/22/2014] [Indexed: 12/12/2022] Open
Abstract
Serological techniques commonly used to quantify influenza-specific antibodies include the Haemagglutination Inhibition (HI), Single Radial Haemolysis (SRH) and Virus Neutralization (VN) assays. HI and SRH are established and reproducible techniques, whereas VN is more demanding. Every new influenza vaccine needs to fulfil the strict criteria issued by the European Medicines Agency (EMA) in order to be licensed. These criteria currently apply exclusively to SRH and HI assays and refer to two different target groups-healthy adults and the elderly, but other vaccine recipient age groups have not been considered (i.e., children). The purpose of this timely review is to highlight the current scenario on correlates of protection concerning influenza vaccines and underline the need to revise the criteria and assays currently in use. In addition to SRH and HI assays, the technical advantages provided by other techniques such as the VN assay, pseudotype-based neutralization assay, neuraminidase and cell-mediated immunity assays need to be considered and regulated via EMA criteria, considering the many significant advantages that they could offer for the development of effective vaccines.
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Affiliation(s)
- Claudia Maria Trombetta
- Department of Molecular and Developmental Medicine, University of Siena, Via Aldo Moro, 53100 Siena, Italy.
| | - Daniele Perini
- VisMederi srl, Enterprise in Life Sciences, Via Fiorentina 1, 53100 Siena, Italy.
| | - Stuart Mather
- Viral Pseudotype Unit, School of Pharmacy, University of Kent, Chatham Maritime, Kent ME4 4TB, UK.
| | - Nigel Temperton
- Viral Pseudotype Unit, School of Pharmacy, University of Kent, Chatham Maritime, Kent ME4 4TB, UK.
| | - Emanuele Montomoli
- Department of Molecular and Developmental Medicine, University of Siena, Via Aldo Moro, 53100 Siena, Italy.
- VisMederi srl, Enterprise in Life Sciences, Via Fiorentina 1, 53100 Siena, Italy.
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18
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Influenza vaccines: a moving interdisciplinary field. Viruses 2014; 6:3809-26. [PMID: 25302957 PMCID: PMC4213563 DOI: 10.3390/v6103809] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 10/01/2014] [Accepted: 10/02/2014] [Indexed: 01/05/2023] Open
Abstract
Vaccination is by far the most effective way of preventing morbidity and mortality due to infection of the upper respiratory tract by influenza virus. Current vaccines require yearly vaccine updates as the influenza virus can escape vaccine-induced humoral immunity due to the antigenic variability of its surface antigens. In case of a pandemic, new vaccines become available too late with current vaccine practices. New technologies that allow faster production of vaccine seed strains in combination with alternative production platforms and vaccine formulations may shorten the time gap between emergence of a new influenza virus and a vaccine becoming available. Adjuvants may allow antigen-sparing, allowing more people to be vaccinated with current vaccine production capacity. Adjuvants and universal vaccines can target immune responses to more conserved influenza epitopes, which eventually will result in broader protection for a longer time. In addition, further immunological studies are needed to gain insights in the immune features that contribute to protection from influenza-related disease and mortality, allowing redefinition of correlates of protection beyond virus neutralization in vitro.
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19
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20
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Sanchez MV, Ebensen T, Schulze K, Cargnelutti D, Blazejewska P, Scodeller EA, Guzmán CA. Intranasal delivery of influenza rNP adjuvanted with c-di-AMP induces strong humoral and cellular immune responses and provides protection against virus challenge. PLoS One 2014; 9:e104824. [PMID: 25140692 PMCID: PMC4139298 DOI: 10.1371/journal.pone.0104824] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Accepted: 07/17/2014] [Indexed: 12/17/2022] Open
Abstract
There is a critical need for new influenza vaccines able to protect against constantly emerging divergent virus strains. This will be sustained by the induction of vigorous cellular responses and humoral immunity capable of acting at the portal of entry of this pathogen. In this study we evaluate the protective efficacy of intranasal vaccination with recombinant influenza nucleoprotein (rNP) co-administrated with bis-(3′,5′)-cyclic dimeric adenosine monophosphate (c-di-AMP) as adjuvant. Immunization of BALB/c mice with two doses of the formulation stimulates high titers of NP-specific IgG in serum and secretory IgA at mucosal sites. This formulation also promotes a strong Th1 response characterized by high secretion of INF-γ and IL-2. The immune response elicited promotes efficient protection against virus challenge. These results suggest that c-di-AMP is a potent mucosal adjuvant which may significantly contribute towards the development of innovative mucosal vaccines against influenza.
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Affiliation(s)
- Maria Victoria Sanchez
- Laboratory of Virology, Institute of Experimental Medicine and Biology of Cuyo (IMBECU-CCT, CONICET), Mendoza, Argentina
- Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Thomas Ebensen
- Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
- * E-mail:
| | - Kai Schulze
- Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Diego Cargnelutti
- Laboratory of Virology, Institute of Experimental Medicine and Biology of Cuyo (IMBECU-CCT, CONICET), Mendoza, Argentina
| | - Paulina Blazejewska
- Boehringer Ingelheim Veterinary Research Center GmbH & Co. KG, Hannover, Germany
| | - Eduardo A. Scodeller
- Laboratory of Virology, Institute of Experimental Medicine and Biology of Cuyo (IMBECU-CCT, CONICET), Mendoza, Argentina
| | - Carlos A. Guzmán
- Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
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21
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van de Sandt CE, Kreijtz JHCM, Geelhoed-Mieras MM, Vogelzang-van Trierum SE, Nieuwkoop NJ, van de Vijver DAMC, Fouchier RAM, Osterhaus ADME, Morein B, Rimmelzwaan GF. Novel G3/DT adjuvant promotes the induction of protective T cells responses after vaccination with a seasonal trivalent inactivated split-virion influenza vaccine. Vaccine 2014; 32:5614-23. [PMID: 25140929 DOI: 10.1016/j.vaccine.2014.08.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Revised: 07/17/2014] [Accepted: 08/06/2014] [Indexed: 12/20/2022]
Abstract
Vaccines used against seasonal influenza are poorly effective against influenza A viruses of novel subtypes that may have pandemic potential. Furthermore, pre(pandemic) influenza vaccines are poorly immunogenic, which can be overcome by the use of adjuvants. A limited number of adjuvants has been approved for use in humans, however there is a need for alternative safe and effective adjuvants that can enhance the immunogenicity of influenza vaccines and that promote the induction of broad-protective T cell responses. Here we evaluated a novel nanoparticle, G3, as an adjuvant for a seasonal trivalent inactivated influenza vaccine in a mouse model. The G3 adjuvant was formulated with or without steviol glycosides (DT, for diterpenoid). The use of both formulations enhanced the virus-specific antibody response to all three vaccine strains considerably. The adjuvants were well tolerated without any signs of discomfort. To assess the protective potential of the vaccine-induced immune responses, an antigenically distinct influenza virus strain, A/Puerto Rico/8/34 (A/PR/8/34), was used for challenge infection. The vaccine-induced antibodies did not cross-react with strain A/PR/8/34 in HI and VN assays. However, mice immunized with the G3/DT-adjuvanted vaccine were partially protected against A/PR/8/34 infection, which correlated with the induction of anamnestic virus-specific CD8(+) T cell responses that were not observed with the use of G3 without DT. Both formulations induced maturation of human dendritic cells and promoted antigen presentation to a similar extent. In conclusion, G3/DT is a promising adjuvant formulation that not only potentiates the antibody response induced by influenza vaccines, but also induces T cell immunity which could afford broader protection against antigenically distinct influenza viruses.
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Affiliation(s)
| | - Joost H C M Kreijtz
- Department of Viroscience, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands
| | | | | | - Nella J Nieuwkoop
- Department of Viroscience, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands
| | | | - Ron A M Fouchier
- Department of Viroscience, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands
| | - Albert D M E Osterhaus
- Department of Viroscience, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands; ViroClinics Biosciences BV, Marconistraat 16, 3029 AK Rotterdam, The Netherlands
| | - Bror Morein
- Infectious Diseases Department of Medical Sciences, Uppsala University, MoreinX, Dag Hammarskjöldsväg 34 A, 751 83 Uppsala, Sweden
| | - Guus F Rimmelzwaan
- Department of Viroscience, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands; ViroClinics Biosciences BV, Marconistraat 16, 3029 AK Rotterdam, The Netherlands.
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Demicheli V, Jefferson T, Al-Ansary LA, Ferroni E, Rivetti A, Di Pietrantonj C. Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev 2014:CD001269. [PMID: 24623315 DOI: 10.1002/14651858.cd001269.pub5] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Different types of influenza vaccines are currently produced worldwide. Vaccination of pregnant women is recommended internationally, while healthy adults are targeted in North America. OBJECTIVES To identify, retrieve and assess all studies evaluating the effects (efficacy, effectiveness and harm) of vaccines against influenza in healthy adults, including pregnant women. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 2), MEDLINE (January 1966 to May 2013) and EMBASE (1990 to May 2013). SELECTION CRITERIA Randomised controlled trials (RCTs) or quasi-RCTs comparing influenza vaccines with placebo or no intervention in naturally occurring influenza in healthy individuals aged 16 to 65 years. We also included comparative studies assessing serious and rare harms. DATA COLLECTION AND ANALYSIS Two review authors independently assessed trial quality and extracted data. MAIN RESULTS We included 90 reports containing 116 data sets; among these 69 were clinical trials of over 70,000 people, 27 were comparative cohort studies (about eight million people) and 20 were case-control studies (nearly 25,000 people). We retrieved 23 reports of the effectiveness and safety of vaccine administration in pregnant women (about 1.6 million mother-child couples).The overall effectiveness of parenteral inactivated vaccine against influenza-like illness (ILI) is limited, corresponding to a number needed to vaccinate (NNV) of 40 (95% confidence interval (CI) 26 to 128). The overall efficacy of inactivated vaccines in preventing confirmed influenza has a NNV of 71 (95% CI 64 to 80). The difference between these two values depends on the different incidence of ILI and confirmed influenza among the study populations: 15.6% of unvaccinated participants versus 9.9% of vaccinated participants developed ILI symptoms, whilst only 2.4% and 1.1%, respectively, developed laboratory-confirmed influenza.No RCTs assessing vaccination in pregnant women were found. The only evidence available comes from observational studies with modest methodological quality. On this basis, vaccination shows very limited effects: NNV 92 (95% CI 63 to 201) against ILI in pregnant women and NNV 27 (95% CI 18 to 185) against laboratory-confirmed influenza in newborns from vaccinated women.Live aerosol vaccines have an overall effectiveness corresponding to a NNV 46 (95% CI 29 to 115).The performance of one-dose or two-dose whole virion pandemic vaccines was higher, showing a NNV of 16 (95% CI 14 to 20) against ILI and a NNV of 35 (95% CI 33 to 47) against influenza, while a limited impact on hospitalisation was found (NNV 94, 95% CI 70 to 1022).Vaccination had a modest effect on time off work and had no effect on hospital admissions or complication rates. Inactivated vaccines caused local harms. No evidence of association with serious adverse events was found, but the harms evidence base was limited.The overall risk of bias in the included trials is unclear because it was not possible to assess the real impact of bias. AUTHORS' CONCLUSIONS Influenza vaccines have a very modest effect in reducing influenza symptoms and working days lost in the general population, including pregnant women. No evidence of association between influenza vaccination and serious adverse events was found in the comparative studies considered in the review. This review includes 90 studies, 24 of which (26.7%) were funded totally or partially by industry. Out of the 48 RCTs, 17 were industry-funded (35.4%).
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Affiliation(s)
- Vittorio Demicheli
- Servizio Regionale di Riferimento per l'Epidemiologia, SSEpi-SeREMI - Cochrane Vaccines Field, Azienda Sanitaria Locale ASL AL, Via Venezia 6, Alessandria, Piemonte, 15121, Italy. .
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23
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van de Sandt CE, Kreijtz JHCM, de Mutsert G, Geelhoed-Mieras MM, Hillaire MLB, Vogelzang-van Trierum SE, Osterhaus ADME, Fouchier RAM, Rimmelzwaan GF. Human cytotoxic T lymphocytes directed to seasonal influenza A viruses cross-react with the newly emerging H7N9 virus. J Virol 2014; 88:1684-93. [PMID: 24257602 PMCID: PMC3911609 DOI: 10.1128/jvi.02843-13] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 11/12/2013] [Indexed: 01/05/2023] Open
Abstract
In February 2013, zoonotic transmission of a novel influenza A virus of the H7N9 subtype was reported in China. Although at present no sustained human-to-human transmission has been reported, a pandemic outbreak of this H7N9 virus is feared. Since neutralizing antibodies to the hemagglutinin (HA) globular head domain of the virus are virtually absent in the human population, there is interest in identifying other correlates of protection, such as cross-reactive CD8(+) T cells (cytotoxic T lymphocytes [CTLs]) elicited during seasonal influenza A virus infections. These virus-specific CD8(+) T cells are known to recognize conserved internal proteins of influenza A viruses predominantly, but it is unknown to what extent they cross-react with the newly emerging H7N9 virus. Here, we assessed the cross-reactivity of seasonal H3N2 and H1N1 and pandemic H1N1 influenza A virus-specific polyclonal CD8(+) T cells, obtained from HLA-typed study subjects, with the novel H7N9 virus. The cross-reactivity of CD8(+) T cells to H7N9 variants of known influenza A virus epitopes and H7N9 virus-infected cells was determined by their gamma interferon (IFN-γ) response and lytic activity. It was concluded that, apart from recognition of individual H7N9 variant epitopes, CD8(+) T cells to seasonal influenza viruses display considerable cross-reactivity with the novel H7N9 virus. The presence of these cross-reactive CD8(+) T cells may afford some protection against infection with the new virus.
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MESH Headings
- Adult
- Amino Acid Sequence
- Antigens, Viral/chemistry
- Antigens, Viral/genetics
- Antigens, Viral/immunology
- Cells, Cultured
- China/epidemiology
- Cross Protection
- Cross Reactions
- Disease Outbreaks
- Epitopes, T-Lymphocyte/chemistry
- Epitopes, T-Lymphocyte/genetics
- Epitopes, T-Lymphocyte/immunology
- Humans
- Influenza A Virus, H1N1 Subtype/chemistry
- Influenza A Virus, H1N1 Subtype/genetics
- Influenza A Virus, H1N1 Subtype/immunology
- Influenza A Virus, H3N2 Subtype/chemistry
- Influenza A Virus, H3N2 Subtype/genetics
- Influenza A Virus, H3N2 Subtype/immunology
- Influenza A Virus, H7N9 Subtype/chemistry
- Influenza A Virus, H7N9 Subtype/genetics
- Influenza A Virus, H7N9 Subtype/immunology
- Influenza A Virus, H7N9 Subtype/isolation & purification
- Influenza, Human/epidemiology
- Influenza, Human/immunology
- Influenza, Human/virology
- Interferon-gamma/immunology
- Male
- Middle Aged
- Molecular Sequence Data
- Seasons
- Sequence Alignment
- T-Lymphocytes, Cytotoxic/immunology
- T-Lymphocytes, Cytotoxic/virology
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Affiliation(s)
| | | | | | | | | | | | | | - Ron A. M. Fouchier
- Viroscience Laboratory, Erasmus MC, Rotterdam, The Netherlands
- ViroClinics Biosciences BV, Rotterdam, The Netherlands
| | - Guus F. Rimmelzwaan
- Viroscience Laboratory, Erasmus MC, Rotterdam, The Netherlands
- ViroClinics Biosciences BV, Rotterdam, The Netherlands
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24
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Abstract
Many vaccine candidates are highly purified, sometimes monomeric antigens and as a result, not very immunogenic. Antigen delivery systems optimize the presentation of antigens. They also play a major role in solving the problem of there being an increasing number of vaccines but limited opportunities in which to include these vaccines in immunization programs. The number of injections is restricted and combining vaccines may lead to immunological and physicochemical incompatibility. In this review, the current status with respect to parenteral and mucosal delivery systems is discussed. These include lipid-based systems such as liposomes and immunostimulating complexes, as well as polymeric microspheres. In addition, developments in needle-free, dermal delivery devices such as jet injectors, microneedles and patches are presented.
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Affiliation(s)
- Gideon Kersten
- Netherlands Vaccine Institute, Unit Research and Development, P.O. Box 457, 3720 BA BILHOVEN, The Netherlands.
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25
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Xiang SD, Scalzo-Inguanti K, Minigo G, Park A, Hardy CL, Plebanski M. Promising particle-based vaccines in cancer therapy. Expert Rev Vaccines 2014; 7:1103-19. [DOI: 10.1586/14760584.7.7.1103] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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26
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Del Giudice G, Rappuoli R. Inactivated and adjuvanted influenza vaccines. Curr Top Microbiol Immunol 2014; 386:151-80. [PMID: 25038938 DOI: 10.1007/82_2014_406] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Inactivated influenza vaccines are produced every year to fight against the seasonal epidemics of influenza. Despite the nonoptimal coverage, even in subjects at risk like the elderly, pregnant women, etc., these vaccines significantly reduce the burden of mortality and morbidity linked to the influenza infection. Importantly, these vaccines have also contributed to reduce the impact of the last pandemics. Nevertheless, the performance of these vaccines can be improved mainly in those age groups, like children and the elderly, in which their efficacy is suboptimal. The use of adjuvants has proven effective to this scope. Oil-in-water adjuvants like MF59 and AS03 have been licensed and widely used, and shown efficacious in preventing influenza infection in the last pandemic. MF59-adjuvanted inactivated vaccine was more efficacious than non-adjuvanted vaccine in preventing influenza infection in young children and in reducing hospitalization due to the influenza infection in the elderly. Other adjuvants are now at different stages of development and some are being tested in clinical trials. The perspective remains to improve the way inactivated vaccines are prepared and to accelerate their availability, mainly in the case of influenza pandemics, and to enhance their efficacy/effectiveness for a more successful impact at the public health level.
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Affiliation(s)
- Giuseppe Del Giudice
- Research and Development, Novartis Vaccines, Via Fiorentina 1, 53100, Siena, Italy,
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27
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Gildea S, Quinlivan M, Murphy BA, Cullinane A. Humoral response and antiviral cytokine expression following vaccination of thoroughbred weanlings--a blinded comparison of commercially available vaccines. Vaccine 2013; 31:5216-22. [PMID: 24021309 DOI: 10.1016/j.vaccine.2013.08.083] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Revised: 08/19/2013] [Accepted: 08/27/2013] [Indexed: 11/29/2022]
Abstract
Previous studies in experimental ponies using interferon gamma (IFN-γ) as a marker for cell mediated immune (CMI) response demonstrated an increase in IFN-γ gene expression following vaccination with an ISCOM subunit, a canarypox recombinant and more recently, an inactivated whole virus vaccine. The objective of this study was to carry out an independent comparison of both humoral antibody and CMI responses elicited following vaccination with all these vaccine presentation systems. Antibody response of 44 Thoroughbred weanlings was monitored for three weeks following the second dose of primary vaccination (V2) by single radial haemolysis (SRH). The pattern of antibody response was similar for all vaccines. The antibody response of horses vaccinated with the inactivated whole virus vaccine (Duvaxyn IE-T Plus) was superior to that of the horses vaccinated with the ISCOM-matrix subunit (Equilis Prequenza Te) and canarypox recombinant (ProteqFlu-Te) vaccine. In this study 39% of weanlings failed to seroconvert following their first dose of primary vaccination (V1). Poor response to vaccination (H3N8) was observed among weanlings vaccinated with Equilis Prequenza Te and ProteqFlu-Te but not among those vaccinated with Duvaxyn IE-T Plus. PAXgene bloods were collected on days 0, 2, 7 and 14 following V1. Gene expression levels of IFN-γ, IL-1β (proinflammatory cytokine) and IL-4 (B cell stimulating cytokine) were measured using RT-PCR. Mean gene expression levels of IL-1β and IL-4 peaked on day 14 post vaccination. The increase in IL-4 gene expression by horses vaccinated with Equilis Prequenza Te was significantly greater to those vaccinated with the other two products. Vaccination with all three vaccines resulted in a significant increase in IFN-γ gene expression which peaked at 7 days post V1. Overall, there was no significant difference in IFN-γ gene expression by the horses vaccinated with the whole inactivated, the subunit and the canarypox recombinant vaccines included in this study.
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Affiliation(s)
- Sarah Gildea
- Virology Unit, The Irish Equine Centre, Johnstown, Naas, Co., Kildare, Ireland
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28
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Szurgot I, Szolajska E, Laurin D, Lambrecht B, Chaperot L, Schoehn G, Chroboczek J. Self-adjuvanting influenza candidate vaccine presenting epitopes for cell-mediated immunity on a proteinaceous multivalent nanoplatform. Vaccine 2013; 31:4338-46. [PMID: 23880363 DOI: 10.1016/j.vaccine.2013.07.021] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Revised: 07/03/2013] [Accepted: 07/10/2013] [Indexed: 11/17/2022]
Abstract
We exploit the features of a virus-like particle, adenoviral dodecahedron (Ad Dd), for engineering a multivalent vaccination platform carrying influenza epitopes for cell-mediated immunity. The delivery platform, Ad Dd, is a proteinaceous, polyvalent, and biodegradable nanoparticle endowed with remarkable endocytosis activity that can be engineered to carry 60 copies of a peptide. Influenza M1 is the most abundant influenza internal protein with the conserved primary structure. Two different M1 immunodominant epitopes were separately inserted in Dd external positions without destroying the particles' dodecahedric structure. Both kinds of DdFluM1 obtained through expression in baculovirus system were properly presented by human dendritic cells triggering efficient activation of antigen-specific T cells responses. Importantly, the candidate vaccine was able to induce cellular immunity in vivo in chickens. These results warrant further investigation of Dd as a platform for candidate vaccine, able to stimulate cellular immune responses.
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Affiliation(s)
- Inga Szurgot
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02106 Warsaw, Poland.
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29
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Campos LMA, Silva CA, Aikawa NE, Jesus AA, Moraes JCB, Miraglia J, Ishida MA, Bueno C, Pereira RMR, Bonfa E. High Disease Activity: An Independent Factor for Reduced Immunogenicity of the Pandemic Influenza A Vaccine in Patients With Juvenile Systemic Lupus Erythematosus. Arthritis Care Res (Hoboken) 2013; 65:1121-7. [DOI: 10.1002/acr.21948] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2012] [Accepted: 12/21/2012] [Indexed: 12/24/2022]
Affiliation(s)
| | - Clovis A. Silva
- Faculdade de Medicina da Universidade de São Paulo; Sao Paulo; Brazil
| | - Nadia E. Aikawa
- Faculdade de Medicina da Universidade de São Paulo; Sao Paulo; Brazil
| | - Adriana A. Jesus
- Faculdade de Medicina da Universidade de São Paulo; Sao Paulo; Brazil
| | | | - Joao Miraglia
- Instituto Butantan, Fundação Butantan; Sao Paulo; Brazil
| | | | - Cleonice Bueno
- Faculdade de Medicina da Universidade de São Paulo; Sao Paulo; Brazil
| | | | - Eloisa Bonfa
- Faculdade de Medicina da Universidade de São Paulo; Sao Paulo; Brazil
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30
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Schotsaert M, Saelens X, Leroux-Roels G. Influenza vaccines: T-cell responses deserve more attention. Expert Rev Vaccines 2013; 11:949-62. [PMID: 23002976 DOI: 10.1586/erv.12.71] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Currently licensed influenza vaccines rely predominantly on the induction of strain-matched hemagglutination inhibition antibody responses. These vaccines have a proven record of safety and efficacy in preventing influenza-induced illness and complications. However, they do not confer protection to all vaccinated individuals, and the protection they afford is short-lived, particularly in older adults. Hemagglutination inhibition titers induced by these vaccines are considered correlates of protection, but recent data demonstrate that this is not always the case. It is clear that better insight is needed into the immune responses that correlate with protection against human influenza. Influenza vaccines that can induce cross-reactive cellular immune responses (CD4(+) and/or CD8(+) T-cell responses) might correct some of the shortcomings of currently used influenza vaccines. In the future, the use of infection-permissive and disease-modifying vaccines that allow for the induction of cross-reactive T-cell responses may become a valuable complement to the administration of trivalent inactivated influenza vaccines.
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31
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Bodewes R, Fraaij PLA, Osterhaus ADME, Rimmelzwaan GF. Pediatric influenza vaccination: understanding the T-cell response. Expert Rev Vaccines 2013; 11:963-71. [PMID: 23002977 DOI: 10.1586/erv.12.69] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Influenza A virus-specific T cells are highly cross-reactive and contribute to heterosubtypic immunity, which may afford protection against novel pandemic strains of influenza virus. However, the magnitude and nature of virus-specific T-cell responses induced by natural infections and/or vaccination in young children is poorly understood. Host factors, such as the development of the immune system during childhood and environmental factors such as exposure rates to influenza viruses and interference by vaccination contribute to shaping the magnitude and specificity of the T-cell response. Here, the authors review several of these factors, including the differences between T-cell responses of young children and adults, the age-dependent frequency of virus-specific T cells and the impact of annual childhood influenza vaccination. In addition, the authors summarize all currently available studies in which influenza vaccine-induced T-cell responses were evaluated. The authors discuss these findings in the light of developing vaccines and vaccination strategies aiming at the induction of protective immunity to seasonal and pandemic influenza viruses of antigenically distinct subtypes.
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Affiliation(s)
- Rogier Bodewes
- Department of Virology, Erasmus MC, Rotterdam, The Netherlands
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32
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Cargnelutti DE, Sánchez MV, Mattion NM, Scodeller EA. Development of a universal CTL-based vaccine for influenza. Bioengineered 2013; 4:374-8. [PMID: 23337287 DOI: 10.4161/bioe.23573] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
In pursuit of better influenza vaccines, many strategies are being studied worldwide. An attractive alternative is the generation of a broadly cross-reactive vaccine based on the induction of cytotoxic T-lymphocytes (CTL) directed against conserved internal antigens of influenza A virus. The feasibility of this approach using recombinant viral vectors has recently been demonstrated in mice and humans by several research groups. However, similar results might also be achieved through immunization with viral proteins expressed in a prokaryotic system formulated with the appropriate adjuvants and delivery systems. This approach would be much simpler and less expensive. Recent results from several laboratories seem to confirm this is as a valid option to be considered.
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Affiliation(s)
- Diego Esteban Cargnelutti
- Institute of Experimental Medicine and Biology of Cuyo (IMBECU-CONICET); Mendoza, Argentina; Animal Virology Center; Institute of Science and Technology Dr César Milstein; CONICET; Buenos Aires, Argentina
| | - María Victoria Sánchez
- Institute of Experimental Medicine and Biology of Cuyo (IMBECU-CONICET); Mendoza, Argentina
| | - Nora Marta Mattion
- Animal Virology Center; Institute of Science and Technology Dr César Milstein; CONICET; Buenos Aires, Argentina
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33
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Micro/nanoparticle adjuvants for antileishmanial vaccines: Present and future trends. Vaccine 2013; 31:735-49. [DOI: 10.1016/j.vaccine.2012.11.068] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2012] [Revised: 11/21/2012] [Accepted: 11/25/2012] [Indexed: 01/04/2023]
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34
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La Gruta N, Kelso A, Brown LE, Chen W, Jackson DC, Turner SJ. Role of CD8(+) T-cell immunity in influenza infection: potential use in future vaccine development. Expert Rev Respir Med 2012; 3:523-37. [PMID: 20477341 DOI: 10.1586/ers.09.44] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Continued circulation of the highly pathogenic avian H5N1 influenza A virus has many people worried that an influenza pandemic is imminent. Compounding this is the realization that H5N1 vaccines based on current influenza vaccine technology (designed to generate protective antibody responses) may be suboptimal at providing protection. As a consequence, there is recent interest in vaccine strategies that elicit cellular immunity, particularly the cytotoxic T lymphocyte response, in an effort to provide protection against a potential pandemic. A major issue is the lack of information about the precise role that these 'hitmen' of the immune system have in protecting against both pandemic and seasonal influenza. We need to know more about how the induction and maintenance of cytotoxic T lymphocytes after influenza infection can impact protection from further infection. The challenge is then to use this information in the design of vaccines that will protect against pandemic influenza and will help optimize CD8(+) killer T-cell responses in other infections.
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Affiliation(s)
- Nicole La Gruta
- Department of Microbiology and Immunology, The University of Melbourne, Royal Parade, Parkville, Victoria 3010, Australia
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35
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van de Sandt CE, Kreijtz JHCM, Rimmelzwaan GF. Evasion of influenza A viruses from innate and adaptive immune responses. Viruses 2012; 4:1438-76. [PMID: 23170167 PMCID: PMC3499814 DOI: 10.3390/v4091438] [Citation(s) in RCA: 151] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2012] [Revised: 08/10/2012] [Accepted: 08/22/2012] [Indexed: 12/16/2022] Open
Abstract
The influenza A virus is one of the leading causes of respiratory tract infections in humans. Upon infection with an influenza A virus, both innate and adaptive immune responses are induced. Here we discuss various strategies used by influenza A viruses to evade innate immune responses and recognition by components of the humoral and cellular immune response, which consequently may result in reduced clearing of the virus and virus-infected cells. Finally, we discuss how the current knowledge about immune evasion can be used to improve influenza A vaccination strategies.
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Affiliation(s)
- Carolien E van de Sandt
- Department of Virology, ErasmusMC, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.
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36
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Jefferson T, Rivetti A, Di Pietrantonj C, Demicheli V, Ferroni E. Vaccines for preventing influenza in healthy children. Cochrane Database Syst Rev 2012; 2012:CD004879. [PMID: 22895945 PMCID: PMC6478137 DOI: 10.1002/14651858.cd004879.pub4] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND The consequences of influenza in children and adults are mainly absenteeism from school and work. However, the risk of complications is greatest in children and people over 65 years of age. OBJECTIVES To appraise all comparative studies evaluating the effects of influenza vaccines in healthy children, assess vaccine efficacy (prevention of confirmed influenza) and effectiveness (prevention of influenza-like illness (ILI)) and document adverse events associated with influenza vaccines. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3) which includes the Acute Respiratory Infections Group's Specialised Register, OLD MEDLINE (1950 to 1965), MEDLINE (1966 to November 2011), EMBASE (1974 to November 2011), Biological Abstracts (1969 to September 2007), and Science Citation Index (1974 to September 2007). SELECTION CRITERIA Randomised controlled trials (RCTs), cohort and case-control studies of any influenza vaccine in healthy children under 16 years of age. DATA COLLECTION AND ANALYSIS Four review authors independently assessed trial quality and extracted data. MAIN RESULTS We included 75 studies with about 300,000 observations. We included 17 RCTs, 19 cohort studies and 11 case-control studies in the analysis of vaccine efficacy and effectiveness. Evidence from RCTs shows that six children under the age of six need to be vaccinated with live attenuated vaccine to prevent one case of influenza (infection and symptoms). We could find no usable data for those aged two years or younger.Inactivated vaccines in children aged two years or younger are not significantly more efficacious than placebo. Twenty-eight children over the age of six need to be vaccinated to prevent one case of influenza (infection and symptoms). Eight need to be vaccinated to prevent one case of influenza-like-illness (ILI). We could find no evidence of effect on secondary cases, lower respiratory tract disease, drug prescriptions, otitis media and its consequences and socioeconomic impact. We found weak single-study evidence of effect on school absenteeism by children and caring parents from work. Variability in study design and presentation of data was such that a meta-analysis of safety outcome data was not feasible. Extensive evidence of reporting bias of safety outcomes from trials of live attenuated influenza vaccines (LAIVs) impeded meaningful analysis. One specific brand of monovalent pandemic vaccine is associated with cataplexy and narcolepsy in children and there is sparse evidence of serious harms (such as febrile convulsions) in specific situations. AUTHORS' CONCLUSIONS Influenza vaccines are efficacious in preventing cases of influenza in children older than two years of age, but little evidence is available for children younger than two years of age. There was a difference between vaccine efficacy and effectiveness, partly due to differing datasets, settings and viral circulation patterns. No safety comparisons could be carried out, emphasising the need for standardisation of methods and presentation of vaccine safety data in future studies. In specific cases, influenza vaccines were associated with serious harms such as narcolepsy and febrile convulsions. It was surprising to find only one study of inactivated vaccine in children under two years, given current recommendations to vaccinate healthy children from six months of age in the USA, Canada, parts of Europe and Australia. If immunisation in children is to be recommended as a public health policy, large-scale studies assessing important outcomes, and directly comparing vaccine types are urgently required. The degree of scrutiny needed to identify all global cases of potential harms is beyond the resources of this review. This review includes trials funded by industry. An earlier systematic review of 274 influenza vaccine studies published up to 2007 found industry-funded studies were published in more prestigious journals and cited more than other studies independently from methodological quality and size. Studies funded from public sources were significantly less likely to report conclusions favourable to the vaccines. The review showed that reliable evidence on influenza vaccines is thin but there is evidence of widespread manipulation of conclusions and spurious notoriety of the studies. The content and conclusions of this review should be interpreted in the light of this finding.
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37
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Induction of virus-specific cytotoxic T lymphocytes as a basis for the development of broadly protective influenza vaccines. J Biomed Biotechnol 2011; 2011:939860. [PMID: 22007149 PMCID: PMC3189652 DOI: 10.1155/2011/939860] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2011] [Revised: 07/01/2011] [Accepted: 08/02/2011] [Indexed: 11/18/2022] Open
Abstract
There is considerable interest in the development of broadly protective influenza vaccines because of the continuous emergence of antigenic drift variants of seasonal influenza viruses and the threat posed by the emergence of antigenically distinct pandemic influenza viruses. It has been recognized more than three decades ago that influenza A virus-specific cytotoxic T lymphocytes recognize epitopes located in the relatively conserved proteins like the nucleoprotein and that they cross-react with various subtypes of influenza A viruses. This implies that these CD8+ T lymphocytes may contribute to protective heterosubtypic immunity induced by antecedent influenza A virus infections. In the present paper, we review the evidence for the role of virus-specific CD8+ T lymphocytes in protective immunity against influenza virus infections and discuss vaccination strategies that aim at the induction of cross-reactive virus-specific T-cell responses.
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38
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Abstract
Adjuvants are becoming the key players of vaccine formulations to enhance the immunogenicity of subunit (peptides, proteins, virus-like particles (VLPs)) and DNA vaccines, as well as to reach the current new goals of preventing and/or treating chronic infectious diseases and cancers. Induction of humoral response, in particular neutralizing antibodies able to inhibit the binding of pathogens to their cellular receptors, remains a major goal of vaccines targeted to prevent acute lytic infections; induction/modulation of cellular immunity is, however, critical to fight latently/chronically infected cells as well as cancer cells. The new adjuvants, included in vaccine preparations, are currently able to modify the presentation of epitopes to the immune system with a specific T(H)1 versus T(H)2 polarization efficacy. A paradigm of the relevance of these new adjuvants is the immunological result obtained with the inclusion of monophosphoryl lipid A in the formulation of L1-based human papillomavirus (HPV)-naked VLPs. In the May issue of this journal, Garcon and colleagues describe the highly enhanced humoral and memory B cellular immunity of the AS04-adjuvanted HPV vaccine, which results in a long-lasting and broad spectrum immunity.
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Affiliation(s)
- Franco M Buonaguro
- Molecular Biology and Viral Oncology, Dpt of Experimental Oncology, Istituto Nazionale Tumori Fond Pascale, Napoli, Italy.
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39
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Systematic identification of immunodominant CD8+ T-cell responses to influenza A virus in HLA-A2 individuals. Proc Natl Acad Sci U S A 2011; 108:9178-83. [PMID: 21562214 DOI: 10.1073/pnas.1105624108] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Immunodominant T-cell responses are important for virus clearance. However, the identification of immunodominant T-cell peptide + HLA glycoprotein epitopes has been hindered by the extent of HLA polymorphism and the limitations of predictive algorithms. A simple, systematic approach has been used here to screen for immunodominant CD8(+) T-cell specificities. The analysis targeted healthy HLA-A2(+) donors to allow comparison with responses to the well-studied influenza matrix protein 1 epitope. Although influenza matrix protein 1 was consistently detected in all individual samples in our study, the response to this epitope was only immunodominant in three of eight, whereas for the other five, prominent CD8(+) T-cell responses tended to focus on various peptides from the influenza nucleoprotein that were not presented by HLA-A2. Importantly, with the four immunodominant T-cell epitopes identified here, only one would have been detected by the current prediction programs. The other three peptides would have been either considered too long or classified as not containing typical HLA binding motifs. Our data stress the importance of systematic analysis for discovering HLA-dependent, immunodominant CD8(+) T-cell epitopes derived from viruses and tumors. Focusing on HLA-A2 and predictive algorithms may be too limiting as we seek to develop targeted immunotherapy and vaccine strategies that depend on T cell-mediated immunity.
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40
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De Temmerman ML, Rejman J, Demeester J, Irvine DJ, Gander B, De Smedt SC. Particulate vaccines: on the quest for optimal delivery and immune response. Drug Discov Today 2011; 16:569-82. [PMID: 21570475 DOI: 10.1016/j.drudis.2011.04.006] [Citation(s) in RCA: 222] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2010] [Revised: 02/10/2011] [Accepted: 04/20/2011] [Indexed: 12/22/2022]
Abstract
Subunit vaccines offer a safer alternative to traditional organism-based vaccines, but their immunogenicity is impaired. This hurdle might be overcome by the use of micro- and nanodelivery systems carrying the antigen(s). This review discusses the rationale for the use of particulate vaccines and provides an overview of antigen-delivery vehicles currently under investigation. It further highlights the cellular uptake, antigen processing and the presentation by antigen-presenting cells because these processes are partially governed by particle characteristics and eventually determine the immunological outcome. Finally, we address the attractive concept of concomitant delivery of antigens and immunopotentiators. The condensed knowledge could be an asset for rationally designing antigen-delivery vehicles to obtain safe and efficacious vaccines.
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Affiliation(s)
- Marie-Luce De Temmerman
- Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium
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41
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Gildea S, Arkins S, Walsh C, Cullinane A. A comparison of antibody responses to commercial equine influenza vaccines following annual booster vaccination of National Hunt Horses – a randomised blind study. Vaccine 2011; 29:3917-22. [DOI: 10.1016/j.vaccine.2011.03.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2010] [Revised: 03/02/2011] [Accepted: 03/02/2011] [Indexed: 10/18/2022]
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42
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Scheible K, Zhang G, Baer J, Azadniv M, Lambert K, Pryhuber G, Treanor JJ, Topham DJ. CD8+ T cell immunity to 2009 pandemic and seasonal H1N1 influenza viruses. Vaccine 2011; 29:2159-68. [PMID: 21211588 PMCID: PMC3061835 DOI: 10.1016/j.vaccine.2010.12.073] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2010] [Revised: 12/08/2010] [Accepted: 12/16/2010] [Indexed: 12/17/2022]
Abstract
A novel strain of H1N1 influenza A virus (pH1N1) emerged in 2009, causing a worldwide pandemic. Several studies suggest that this virus is antigenically more closely related to human influenza viruses that circulated prior to 1957 than viruses of more recent seasonal influenza varieties. The extent to which individuals who are naïve to the 2009 pH1N1 virus carry cross-reactive CD8+ T cells is not known, but a certain degree of reactivity would be expected since there is substantial conservation among the internal proteins of the virus. In the present study, we examined the production of multiple cytokines in response to virus from CD8+ T cells in healthy adult subjects, between 18 and 50 years of age (born post 1957), who had no evidence of exposure to the 2009 pH1N1 virus, and had blood collected prior to the emergence of the pandemic in April of 2009. Human peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with a panel of live viruses, and assayed by intracellular cytokine staining and flow cytometry. Although results were variable, most subjects exhibited cytokine positive CD8+ T cells in response to pH1N1. Cytokine producing cells were predominantly single positive (IL2, IFNγ, or TNFα); triple-cytokine producing cells were relatively rare. This result suggests that although many adults carry cross-reactive T cells against the emergent pandemic virus, these cells are in a functionally limited state, possibly because these subjects have not had recent exposure to either seasonal or pandemic influenza strains.
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Affiliation(s)
- Kristin Scheible
- New York Influenza Center of Excellence, David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology; University of Rochester Medical Center, Rochester, NY 14642, USA
- Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Gang Zhang
- Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Jane Baer
- New York Influenza Center of Excellence, David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology; University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Mitra Azadniv
- New York Influenza Center of Excellence, David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology; University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Kris Lambert
- New York Influenza Center of Excellence, David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology; University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Gloria Pryhuber
- Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY 14642, USA
- Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - John J. Treanor
- New York Influenza Center of Excellence, David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology; University of Rochester Medical Center, Rochester, NY 14642, USA
- Division of Infectious Diseases, Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - David J. Topham
- New York Influenza Center of Excellence, David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology; University of Rochester Medical Center, Rochester, NY 14642, USA
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Kodama S, Hirano T, Noda K, Umemoto S, Suzuki M. Nasal immunization with plasmid DNA encoding P6 protein and immunostimulatory complexes elicits nontypeable Haemophilus influenzae-specific long-term mucosal immune responses in the nasopharynx. Vaccine 2011; 29:1881-90. [PMID: 21237276 DOI: 10.1016/j.vaccine.2010.12.129] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2010] [Revised: 11/26/2010] [Accepted: 12/30/2010] [Indexed: 11/16/2022]
Abstract
Nasal vaccination is an effective therapeutic regimen for preventing upper respiratory infection, while DNA vaccines represent a new approach for controlling infectious diseases. Here, we examined the efficacy of nasally administered DNA vaccine on upper respiratory infections. A DNA plasmid encoding the P6 outer membrane protein of nontypeable Haemophilus influenzae (NTHi) was constructed. Mice were immunized 3 times intranasally with the DNA plasmid and Matrix-M, an immunostimulatory complex adjuvant. P6-specific immune responses were examined using purified P6 protein. Nasal-associated lymphoid tissue (NALT) CD4(+) T cells were purified and incubated with feeder cells in the presence of P6, and the expression of cytokine mRNA was examined. In addition, NTHi challenges were performed and the level of NTHi was quantified in nasal washes. P6-specific nasal wash IgA and serum IgG were elevated following immunization with the DNA plasmid and Matrix-M. The number of specific IgA-producing cells increased in the nasal passages of the immunized mice. In addition to Th1 and Th2 cytokine expression, IL-17 was detected in P6-specific NALT CD4(+) T cells. Moreover, DNA vaccination enhanced bacterial clearance. These findings suggest that a successful DNA vaccination protocol has been developed for inducing in vivo immune responses against NTHi. Nasal vaccination with P6 DNA vaccine and Matrix-M might be a new effective regimen for the induction of specific protective immunity in the upper respiratory tract.
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Affiliation(s)
- Satoru Kodama
- Department of Otolaryngology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hazama-cho, Yufu, Oita 879-5593, Japan.
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Lu CC, Wang YC, Lai JH, Lee TSH, Lin HT, Chang DM. A/H1N1 influenza vaccination in patients with systemic lupus erythematosus: Safety and immunity. Vaccine 2011; 29:444-50. [DOI: 10.1016/j.vaccine.2010.10.081] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2010] [Revised: 10/28/2010] [Accepted: 10/29/2010] [Indexed: 02/01/2023]
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Jefferson T, Di Pietrantonj C, Rivetti A, Bawazeer GA, Al-Ansary LA, Ferroni E. Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev 2010:CD001269. [PMID: 20614424 DOI: 10.1002/14651858.cd001269.pub4] [Citation(s) in RCA: 183] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND Different types of influenza vaccines are currently produced worldwide. Healthy adults are presently targeted mainly in North America. OBJECTIVES Identify, retrieve and assess all studies evaluating the effects of vaccines against influenza in healthy adults. SEARCH STRATEGY We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2010, issue 2), MEDLINE (January 1966 to June 2010) and EMBASE (1990 to June 2010). SELECTION CRITERIA Randomised controlled trials (RCTs) or quasi-RCTs comparing influenza vaccines with placebo or no intervention in naturally-occurring influenza in healthy individuals aged 16 to 65 years. We also included comparative studies assessing serious and rare harms. DATA COLLECTION AND ANALYSIS Two review authors independently assessed trial quality and extracted data. MAIN RESULTS We included 50 reports. Forty (59 sub-studies) were clinical trials of over 70,000 people. Eight were comparative non-RCTs and assessed serious harms. Two were reports of harms which could not be introduced in the data analysis. In the relatively uncommon circumstance of vaccine matching the viral circulating strain and high circulation, 4% of unvaccinated people versus 1% of vaccinated people developed influenza symptoms (risk difference (RD) 3%, 95% confidence interval (CI) 2% to 5%). The corresponding figures for poor vaccine matching were 2% and 1% (RD 1, 95% CI 0% to 3%). These differences were not likely to be due to chance. Vaccination had a modest effect on time off work and had no effect on hospital admissions or complication rates. Inactivated vaccines caused local harms and an estimated 1.6 additional cases of Guillain-Barré Syndrome per million vaccinations. The harms evidence base is limited. AUTHORS' CONCLUSIONS Influenza vaccines have a modest effect in reducing influenza symptoms and working days lost. There is no evidence that they affect complications, such as pneumonia, or transmission.WARNING: This review includes 15 out of 36 trials funded by industry (four had no funding declaration). An earlier systematic review of 274 influenza vaccine studies published up to 2007 found industry funded studies were published in more prestigious journals and cited more than other studies independently from methodological quality and size. Studies funded from public sources were significantly less likely to report conclusions favorable to the vaccines. The review showed that reliable evidence on influenza vaccines is thin but there is evidence of widespread manipulation of conclusions and spurious notoriety of the studies. The content and conclusions of this review should be interpreted in light of this finding.
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Affiliation(s)
- Tom Jefferson
- Vaccines Field, The Cochrane Collaboration, Via Adige 28a, Anguillara Sabazia, Roma, Italy, 00061
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Controlling influenza by cytotoxic T-cells: calling for help from destroyers. J Biomed Biotechnol 2010; 2010:863985. [PMID: 20508820 PMCID: PMC2875772 DOI: 10.1155/2010/863985] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2009] [Accepted: 03/03/2010] [Indexed: 12/26/2022] Open
Abstract
Influenza is a vaccine preventable disease that causes severe illness and excess mortality in humans. Licensed influenza vaccines induce humoral immunity and protect against strains that antigenically match the major antigenic components of the vaccine, but much less against antigenically diverse influenza strains. A vaccine that protects against different influenza viruses belonging to the same subtype or even against viruses belonging to more than one subtype would be a major advance in our battle against influenza. Heterosubtypic immunity could be obtained by cytotoxic T-cell (CTL) responses against conserved influenza virus epitopes. The molecular mechanisms involved in inducing protective CTL responses are discussed here. We also focus on CTL vaccine design and point to the importance of immune-related databases and immunoinformatics tools in the quest for new vaccine candidates. Some techniques for analysis of T-cell responses are also highlighted, as they allow estimation of cellular immune responses induced by vaccine preparations and can provide correlates of protection.
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The first safe inactivated equine influenza vaccine formulation adjuvanted with ISCOM-Matrix that closes the immunity gap. Vaccine 2009; 27:5530-7. [DOI: 10.1016/j.vaccine.2009.06.085] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2009] [Revised: 06/02/2009] [Accepted: 06/25/2009] [Indexed: 11/22/2022]
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Nordly P, Madsen HB, Nielsen HM, Foged C. Status and future prospects of lipid-based particulate delivery systems as vaccine adjuvants and their combination with immunostimulators. Expert Opin Drug Deliv 2009; 6:657-72. [DOI: 10.1517/17425240903018863] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Sun HX, Xie Y, Ye YP. ISCOMs and ISCOMATRIX. Vaccine 2009; 27:4388-401. [PMID: 19450632 DOI: 10.1016/j.vaccine.2009.05.032] [Citation(s) in RCA: 172] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2008] [Revised: 02/22/2009] [Accepted: 05/09/2009] [Indexed: 10/25/2022]
Abstract
Immunostimulatory complexes (ISCOMs) are particulate antigen delivery systems composed of antigen, cholesterol, phospholipid and saponin, while ISCOMATRIX is a particulate adjuvant comprising cholesterol, phospholipid and saponin but without antigen. The combination of an antigen with ISCOMATRIX is called an ISCOMATRIX vaccine. ISCOMs and ISCOMATRIX combine the advantages of a particulate carrier system with the presence of an in-built adjuvant (Quil A) and consequently have been found to be more immunogenic, while removing its haemolytic activity of the saponin, producing less toxicity. ISCOMs and ISCOMATRIX vaccines have now been shown to induce strong antigen-specific cellular or humoral immune responses to a broad range of antigens of viral, bacterial, parasite origin or tumor in a number of animal species including non-human primates and humans. These vaccines produced by well controlled and reproducible processes have also been evaluated in human clinical trials. In this review, we summarize the recent progress of ISCOMs and ISCOMATRIX, including preparation technology as well as their application in humans and veterinary vaccine designs with particular emphasis on the current understanding of the properties and features of ISCOMs and ISCOMATRIX vaccines to induce immune responses. The mechanisms of adjuvanticity are also discussed in the light of recent findings.
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Affiliation(s)
- Hong-Xiang Sun
- Key Laboratory of Animal Epidemic Etiology & Immunological Prevention of Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Kaixuan Road 268, Hangzhou 310029, Zhejiang, China.
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Prospects for an influenza vaccine that induces cross-protective cytotoxic T lymphocytes. Immunol Cell Biol 2009; 87:300-8. [PMID: 19308073 DOI: 10.1038/icb.2009.16] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Our approach to vaccination against influenza is unique. For no other pathogen do we construct and produce a new vaccine every year in the face of uncertainty about the strains that will be circulating when it is used. The huge global cooperative effort that underpins this process reflects our awareness of the need to control this major pathogen. Moreover, the threat of devastation by a pandemic due to a newly emerging viral subtype has triggered an intense effort to improve and accelerate the production of vaccines for use if a pandemic arises. However, type A influenza viruses responsible for seasonal epidemics and those with the potential to cause a pandemic share amino acid sequences that form the targets of cytotoxic T lymphocytes (CTL). CTL activated by currently circulating viruses, therefore, offer a possible means to limit the impact of infection with future variant seasonal strains and even new subtypes. This review examines how cross-protective CTL can be exploited to improve influenza vaccination and issues that need to be considered when attempting to induce this type of immunity. We discuss the role of CTL responses in viral control and review the current knowledge relating to specificity and longevity of memory CD8(+) T cells, how vaccine antigen can be loaded into antigen-presenting cells to prime these responses and factors influencing the class of response induced. Application of these principles to the next generation of influenza vaccines should lead to much greater control of infection.
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