Immunogenicity Measures of Influenza Vaccines: A Study of 1164 Registered Clinical Trials
Abstract
:1. Introduction
2. Materials and Methods
2.1. Search Strategy, Eligibility Criteria and Data Extraction
2.2. Study Variables
2.3. Data Analysis
3. Results
3.1. Selection of Clinical Trials and Immunological Assays Used
3.2. Determinants of the Immunological Assays Used
4. Discussion
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Cassini, A.; Colzani, E.; Pini, A.; Mangen, M.J.; Plass, D.; McDonald, S.A.; Maringhini, G.; van Lier, A.; Haagsma, J.A.; Havelaar, A.H.; et al. Impact of infectious diseases on population health using incidence-based disability-adjusted life years (DALYs): Results from the Burden of Communicable Diseases in Europe study, European Union and European Economic Area countries, 2009 to 2013. Eur. Surveill. 2018, 23. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- World Health Organization (WHO). Vaccines against influenza WHO position paper—November 2012. Wkly. Epidemiol. Rec. 2012, 87, 461–476. [Google Scholar]
- Plotkin, S.A. Correlates of protection induced by vaccination. Clin. Vaccine Immunol. 2010, 17, 1055–1065. [Google Scholar] [CrossRef] [Green Version]
- Domnich, A.; Manini, I.; Calabrò, G.E.; de Waure, C.; Montomoli, E. Mapping host-related correlates of influenza vaccine-induced immune response: An umbrella review of the available systematic reviews and meta-analyses. Vaccines 2019, 7, 215. [Google Scholar] [CrossRef] [Green Version]
- Trombetta, C.M.; Remarque, E.J.; Mortier, D.; Montomoli, E. Comparison of hemagglutination inhibition, single radial hemolysis, virus neutralization assays, and ELISA to detect antibody levels against seasonal influenza viruses. Influenza Other Respir. Viruses 2018, 12, 675–686. [Google Scholar] [CrossRef] [PubMed]
- US Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research. Guidance for Industry: Clinical Data Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines. Available online: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-data-needed-support-licensure-seasonal-inactivated-influenza-vaccines (accessed on 9 May 2019).
- European Medicines Agency (EMA); Committee for Medicinal Products for Human Use (CHMP). Guideline on Influenza Vaccines: Non-Clinical and Clinical Module. Available online: https://www.ema.europa.eu/en/documents/scientific-guideline/influenza-vaccines-non-clinical-clinical-module_en.pdf (accessed on 9 May 2020).
- Hobson, D.; Curry, R.L.; Beare, A.S.; Ward-Gardner, A. The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J. Hyg. 1972, 70, 767–777. [Google Scholar] [CrossRef] [Green Version]
- de Jong, J.C.; Palache, A.M.; Beyer, W.E.; Rimmelzwaan, G.F.; Boon, A.C.; Osterhaus, A.D. Haemagglutination-inhibiting antibody to influenza virus. Dev. Biol. 2003, 115, 63–73. [Google Scholar]
- Coudeville, L.; Bailleux, F.; Riche, B.; Megas, F.; Andre, P.; Ecochard, R. Relationship between haemagglutination-inhibiting antibody titres and clinical protection against influenza: Development and application of a Bayesian random-effects model. BMC Med. Res. Methodol. 2010, 10, 8. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Black, S.; Nicolay, U.; Vesikari, T.; Knuf, M.; Del Giudice, G.; Della Cioppa, G.; Tsai, T.; Clemens, R.; Rappuoli, R. Hemagglutination inhibition antibody titers as a correlate of protection for inactivated influenza vaccines in children. Pediatr. Infect. Dis. J. 2011, 30, 1081–1085. [Google Scholar] [CrossRef] [PubMed]
- Delem, A.; Jovanovic, D. Correlation between rate of infection and preexisting titer of serum antibody as determined by single radial hemolysis during and epidemic of influenza A/Victoria/3/75. J. Infect. Dis. 1978, 137, 194–196. [Google Scholar] [CrossRef] [PubMed]
- Cheng, L.W.; Huang, S.W.; Huang, L.M.; Chang, L.Y.; Shao, P.L.; Kiang, D.; Wang, J.R. Comparison of neutralizing and hemagglutination-inhibiting antibody responses for evaluating the seasonal influenza vaccine. J. Virol. Methods 2012, 182, 43–49. [Google Scholar] [CrossRef]
- Sicca, F.; Martinuzzi, D.; Montomoli, E.; Huckriede, A. Comparison of influenza-specific neutralizing antibody titers determined using different assay readouts and hemagglutination inhibition titers: Good correlation but poor agreement. Vaccine 2020, 38, 2527–2541. [Google Scholar] [CrossRef]
- Dunning, A.J.; DiazGranados, C.A.; Voloshen, T.; Hu, B.; Landolfi, V.A.; Talbot, H.K. Correlates of protection against influenza in the elderly: Results from an influenza vaccine efficacy trial. Clin. Vaccine Immunol. 2016, 23, 228–235. [Google Scholar] [CrossRef] [Green Version]
- Eichelberger, M.C.; Wan, H. Influenza neuraminidase as a vaccine antigen. Curr. Top. Microbiol. Immunol. 2015, 386, 275–299. [Google Scholar] [CrossRef]
- Eichelberger, M.C.; Monto, A.S. Neuraminidase, the forgotten surface antigen, emerges as an influenza vaccine target for broadened protection. Clin. Infect. Dis. 2019, 219 (Suppl. 1), S75–S80. [Google Scholar] [CrossRef] [Green Version]
- Gianchecchi, E.; Torelli, A.; Montomoli, E. The use of cell-mediated immunity for the evaluation of influenza vaccines: An upcoming necessity. Hum. Vaccin. Immunother. 2019, 15, 1021–1030. [Google Scholar] [CrossRef]
- United States National Library of Medicine. ClinicalTrials.gov. Available online: https://clinicaltrials.gov/ct2/home (accessed on 9 May 2020).
- Kang, S.M.; Kim, M.C.; Compans, R.W. Virus-like particles as universal influenza vaccines. Expert Rev. Vaccines 2012, 11, 995–1007. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- R Core Team. R: A Language and Environment for Statistical Computing. Available online: http://www.R-project.org/ (accessed on 9 May 2020).
- Rowe, T.; Abernathy, R.A.; Hu-Primmer, J.; Thompson, W.W.; Lu, X.; Lim, W.; Fukuda, K.; Cox, N.J.; Katz, J.M. Detection of antibody to avian influenza A (H5N1) virus in human serum by using a combination of serologic assays. J. Clin. Microbiol. 1999, 37, 937–943. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Stephenson, I.; Heath, A.; Major, D.; Newman, R.W.; Hoschler, K.; Junzi, W.; Katz, J.M.; Weir, J.P.; Zambon, M.C.; Wood, J.M. Reproducibility of serologic assays for influenza virus A (H5N1). Emerg. Infect. Dis. 2009, 15, 1252–1259. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Trombetta, C.M.; Perini, D.; Mather, S.; Temperton, N.; Montomoli, E. Overview of serological techniques for influenza vaccine evaluation: Past, present and future. Vaccines 2014, 2, 707–734. [Google Scholar] [CrossRef] [Green Version]
- World Health Organization. Vaccines for Pandemic Influenza. Available online: https://apps.who.int/iris/bitstream/handle/10665/69821/WHO_CDS_CSR_GIP_2004_3_eng.pdf;jsessionid=DD4F77C9249E85AB9796B60F4497FBD6?sequence=1 (accessed on 9 May 2020).
- Sui, J.; Hwang, W.C.; Perez, S.; Wei, G.; Aird, D.; Chen, L.M.; Santelli, E.; Stec, B.; Cadwell, G.; Ali, M.; et al. Structural and functional bases for broad-spectrum neutralization of avian and human influenza a viruses. Nat. Struct. Mol. Biol. 2009, 16, 265–273. [Google Scholar] [CrossRef] [PubMed]
- Nunes, M.C.; Weinberg, A.; Cutland, C.L.; Jones, S.; Wang, D.; Dighero-Kemp, B.; Levine, M.Z.; Wairagkar, N.; Madhi, S.A. Neutralization and hemagglutination-inhibition antibodies following influenza vaccination of HIV-infected and HIV-uninfected pregnant women. PLoS ONE 2018, 13, e0210124. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hsu, J.P.; Zhao, X.; Chen, M.I.; Cook, A.R.; Lee, V.; Lim, W.Y.; Tan, L.; Barr, I.G.; Jiang, L.; Tan, C.L.; et al. Rate of decline of antibody titers to pandemic influenza A (H1N1-2009) by hemagglutination inhibition and virus microneutralization assays in a cohort of seroconverting adults in Singapore. BMC Infect. Dis. 2014, 14, 414. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Verschoor, C.P.; Singh, P.; Russell, M.L.; Bowdish, D.M.; Brewer, A.; Cyr, L.; Ward, B.J.; Loeb, M. Microneutralization assay titres correlate with protection against seasonal influenza H1N1 and H3N2 in children. PLoS ONE 2015, 10, e0131531. [Google Scholar] [CrossRef]
- Nicolay, U.; Heijnen, E.; Nacci, P.; Patriarca, P.A.; Leav, B. Immunogenicity of aIIV3, MF59-adjuvanted seasonal trivalent influenza vaccine, in older adults ≥65 years of age: Meta-analysis of cumulative clinical experience. Int. J. Infect. Dis. 2019, 85S, S1–S9. [Google Scholar] [CrossRef] [Green Version]
- Banzhoff, A.; Nacci, P.; Podda, A. A new MF59-adjuvanted influenza vaccine enhances the immune response in the elderly with chronic diseases: Results from an immunogenicity meta-analysis. Gerontology 2003, 49, 177–184. [Google Scholar] [CrossRef]
- Ansaldi, F.; Zancolli, M.; Durando, P.; Montomoli, E.; Sticchi, L.; Del Giudice, G.; Icardi, G. Antibody response against heterogeneous circulating influenza virus strains elicited by MF59- and non-adjuvanted vaccines during seasons with good or partial matching between vaccine strain and clinical isolates. Vaccine 2010, 28, 4123–4129. [Google Scholar] [CrossRef]
- Zedda, L.; Forleo-Neto, E.; Vertruyen, A.; Raes, M.; Marchant, A.; Jansen, W.; Clouting, H.; Arora, A.; Beatty, M.E.; Galli, G.; et al. Dissecting the immune response to MF59-adjuvanted and nonadjuvanted seasonal influenza vaccines in children less than three years of age. Pediatr. Infect. Dis. J. 2015, 34, 73–78. [Google Scholar] [CrossRef]
- Del Giudice, G.; Rappuoli, R.; Didierlaurent, A.M. Correlates of adjuvanticity: A review on adjuvants in licensed vaccines. Semin. Immunol. 2018, 39, 14–21. [Google Scholar] [CrossRef]
- Weinberg, A.; Curtis, D.; Ning, M.F.; Claypool, D.J.; Jalbert, E.; Patterson, J.; Frank, D.N.; Ir, D.; Armon, C. Immune responses to circulating and vaccine viral strains in HIV-infected and uninfected children and youth who received the 2013/2014 quadrivalent live-attenuated influenza vaccine. Front. Immunol. 2016, 7, 142. [Google Scholar] [CrossRef] [Green Version]
- Wright, P.F.; Hoen, A.G.; Ilyushina, N.A.; Brown, E.P.; Ackerman, M.E.; Wieland-Alter, W.; Connor, R.I.; Jegaskanda, S.; Rosenberg-Hasson, Y.; Haynes, B.C.; et al. Correlates of immunity to influenza as determined by challenge of children with live, attenuated influenza vaccine. Open Forum Infect. Dis. 2016, 23, ofw108. [Google Scholar] [CrossRef] [Green Version]
- Mohn, K.G.; Smith, I.; Sjursen, H.; Cox, R.J. Immune responses after live attenuated influenza vaccination. Hum. Vaccin. Immunother. 2018, 14, 571–578. [Google Scholar] [CrossRef] [PubMed]
- Ambrose, C.S.; Wu, X.; Jones, T.; Mallory, R.M. The role of nasal IgA in children vaccinated with live attenuated influenza vaccine. Vaccine 2012, 30, 6794–6801. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Forrest, B.D.; Pride, M.W.; Dunning, A.J.; Capeding, M.R.; Chotpitayasunondh, T.; Tam, J.S.; Rappaport, R.; Eldridge, J.H.; Gruber, W.C. Correlation of cellular immune responses with protection against culture-confirmed influenza virus in young children. Clin. Vaccine Immunol. 2008, 15, 1042–1053. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pica, N.; Palese, P. Toward a universal influenza virus vaccine: Prospects and challenges. Annu. Rev. Med. 2013, 64, 189–202. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gilbert, S.C. Advances in the development of universal influenza vaccines. Influenza Other Respir. Viruses 2013, 7, 750–758. [Google Scholar] [CrossRef]
- Zhang, H.; Wang, L.; Compans, R.W.; Wang, B.Z. Universal influenza vaccines, a dream to be realized soon. Viruses 2014, 6, 1974–1991. [Google Scholar] [CrossRef] [Green Version]
- Krammer, F.; Weir, J.P.; Engelhardt, O.; Katz, J.M.; Cox, R.J. Meeting report and review: Immunological assays and correlates of protection for next-generation influenza vaccines. Influenza Other Respir. Viruses 2020, 14, 237–243. [Google Scholar] [CrossRef]
- World Health Organization (WHO). Clinical Evaluation of Vaccines. Available online: https://www.who.int/biologicals/vaccines/clinical_evaluation/en/ (accessed on 9 May 2020).
- World Health Organization (WHO). Guidelines on Clinical Evaluation of Vaccines: Regulatory Expectations. Available online: https://www.who.int/biologicals/expert_committee/Clinical_changes_IK_final.pdf (accessed on 9 May 2020).
- Viergever, R.F.; Karam, G.; Reis, A.; Ghersi, D. The quality of registration of clinical trials: Still a problem. PLoS ONE 2014, 9, e84727. [Google Scholar] [CrossRef] [Green Version]
- Jørgensen, L.; Gøtzsche, P.C.; Jefferson, T. Index of the human papillomavirus (HPV) vaccine industry clinical study programmes and non-industry funded studies: A necessary basis to address reporting bias in a systematic review. Syst. Rev. 2018, 7, 8. [Google Scholar] [CrossRef] [Green Version]
- Harrell, F.E., Jr.; Lee, K.L.; Mark, D.B. Multivariable prognostic models: Issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat. Med. 1996, 15, 361–387. [Google Scholar] [CrossRef]
- Puhr, R.; Heinze, G.; Nold, M.; Lusa, L.; Geroldinger, A. Firth’s logistic regression with rare events: Accurate effect estimates and predictions? Stat. Med. 2017, 36, 2302–2317. [Google Scholar] [CrossRef] [PubMed]
- European Commission. Report of the Expert Panel on Effective Ways of Investing in Health (EXPH) on Disruptive Innovation: Considerations for Health and Health Care in Europe. Available online: https://ec.europa.eu/health/expert_panel/sites/expertpanel/files/012_disruptive_innovation_en.pdf (accessed on 9 May 2020).
- Roehrich, J.K.; Lewis, M.A.; George, G. Are public-private partnerships a healthy option? A systematic literature review. Soc. Sci. Med. 2014, 113, 110–119. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Parameter | % (N) | 95% CI |
---|---|---|
Humoral response only | 76.5 (891) | 74.0–79.0 |
Cell-mediated response only | 3.0 (35) | 2.1–4.2 |
One assay only | 61.3 (714) | 58.5–64.2 |
Two assays | 26.8 (312) | 24.3–29.4 |
Three assays or more | 11.9 (138) | 10.1–13.9 |
HAI assay | 80.6 (938) | 78.2–82.8 |
HAI assay only | 47.8 (556) | 44.9–50.7 |
VN assays | 21.7 (253) | 19.4–24.2 |
VN assays only | 1.0 (12) | 0.5–1.8 |
ELISA | 10.1 (117) | 8.4–11.9 |
ELISA only | 0.9 (10) | 0.4–1.6 |
SRH assay | 4.6 (54) | 3.5–6.0 |
SRH assay only | 1.2 (14) | 0.7–2.0 |
Anti-NA response | 1.7 (20) | 1.1–2.6 |
Anti-NA response only | 0 (0) | 0.0–0.3 |
Humoral response assay unclear | 11.4 (133) | 9.7–13.4 |
Variable | Level | Best-Subset Model | Full Model | ||
---|---|---|---|---|---|
aOR (95% CI) | P | aOR (95% CI) | P | ||
Vaccine | Monovalent a | 5.68 (3.89–8.30) | <0.001 *** | 3.35 (1.75–6.44) | <0.001 *** |
Trivalent a | – | – | 0.70 (0.41–1.22) | 0.21 | |
Quadrivalent | – | – | 1.07 (0.57–1.98) | 0.84 | |
Adjuvanted a | 1.48 (1.02–2.15) | 0.038 * | 1.65 (1.10–2.46) | 0.015 * | |
Intradermal a | – | – | 1.04 (0.45–2.37) | 0.93 | |
Live/intranasal a | – | – | 1.43 (0.81–2.54) | 0.22 | |
Cell-derived/recombinant a | 2.03 (1.37–3.00) | <0.001 *** | 1.82 (1.18–2.80) | 0.006 ** | |
Universal candidates a | – | – | 0.55 (0.19–1.63) | 0.28 | |
Age | Any | Ref | – | Ref | – |
Children only | 3.49 (1.22–9.99) | 0.020 * | 2.92 (0.97–8.83) | 0.058 | |
Adults only | 3.59 (1.32–9.75) | 0.012 * | 2.90 (1.01–8.34) | 0.048 * | |
Elderly only | 5.58 (1.85–16.89) | 0.002 ** | 4.71 (1.49–14.88) | 0.008 ** | |
Children and adults | 1.83 (0.52–6.42) | 0.35 | 1.68 (0.45–6.22) | 0.44 | |
Adults and elderly | 1.67 (0.60–4.65) | 0.33 | 1.59 (0.54–4.66) | 0..40 | |
Study type | Observational | – | – | Ref | – |
Interventional | – | – | 0.63 (0.26–1.49) | 0.29 | |
Study phase | 1 | – | – | Ref | – |
2 | – | – | 0.72 (0.45–1.16) | 0.17 | |
3 | – | – | 0.49 (0.26–0.90) | 0.022 * | |
4 | – | – | 0.36 (0.20–0.64) | <0.001 *** | |
Industry sponsored | No | Ref | – | Ref | – |
Yes | 0.48 (0.33–0.68) | <0.001 *** | 0.40 (0.26–0.90) | <0.001 *** | |
Time | Year b | 1.08 (1.04–1.13) | <0.001 *** | 1.07 (1.01–1.12) | 0.016 * |
Sample size | <180 | – | – | Ref | – |
≥180 | – | – | 1.27 (0.87–1.86) | 0.21 | |
Study location | Multicontinental | – | – | Ref | – |
Europe | – | – | 0.67 (0.28–1.58) | 0.36 | |
US and Canada | – | – | 0.62 (0.27–1.46) | 0.27 | |
Asia and Pacific | – | – | 0.85 (0.36–2.04) | 0.72 | |
Rest of the world | – | – | 0.09 (0.02–0.49) | 0.006 ** | |
Pseudo-R2, % | 30.0 | 35.3 | |||
BIC | 1008.6 | 1074.2 |
Variable | Level | Best-Subset Model | Full Model | ||
---|---|---|---|---|---|
aOR (95% CI) | P | aOR (95% CI) | P | ||
Vaccine | Monovalent a | – | – | 1.04 (0.37–2.96) | 0.94 |
Trivalent a | – | – | 1.62 (0.65–4.04) | 0.30 | |
Quadrivalent | – | – | 0.82 (0.34–2.01) | 0.67 | |
Adjuvanted a | 0.34 (0.17–0.67) | 0.002 ** | 0.32 (0.15–0.65) | 0.002 ** | |
Intradermal a | – | – | 0.30 (0.06–1.37) | 0.12 | |
Live/intranasal a | 8.28 (4.86–14.11) | <0.001 *** | 8.60 (4.75–15.56) | <0.001 *** | |
Cell-derived/recombinant a | 2.41 (1.37–4.24) | 0.002 ** | 2.28 (1.19–4.37) | 0.013 * | |
Universal candidates a | – | – | 1.97 (0.57–6.80) | 0.28 | |
Age | Any | – | – | Ref | – |
Children only | – | – | 1.40 (0.33–6.02) | 0.65 | |
Adults only | – | – | 1.34 (0.34–5.35) | 0.68 | |
Elderly only | – | – | 2.62 (0.56–12.29) | 0.22 | |
Children and adults | – | – | 1.26 (0.25–6.33) | 0.78 | |
Adults and elderly | – | – | 1.06 (0.26–4.35) | 0.94 | |
Study type | Observational | – | – | Ref | – |
Interventional | – | – | 0.57 (0.21–1.55) | 0.27 | |
Study phase | 1 | Ref | – | Ref | – |
2 | 0.36 (0.19–0.66) | 0.001 ** | 0.37 (0.19–0.71) | 0.003 ** | |
3 | 0.10 (0.04–0.29) | <0.001 *** | 0.12 (0.04–0.36) | <0..001 *** | |
4 | 0.32 (0.18–0.59) | <0.001 *** | 0.28 (0.14–0.59) | <0.001 *** | |
Industry sponsored | No | Ref | – | Ref | – |
Yes | 0.45 (0.27–0.75) | 0.002 ** | 0.46 (0.27–0.81) | 0.007 ** | |
Time | Year b | – | – | 1.06 (0.99–1.14) | 0.090 |
Sample size | <180 | – | – | Ref | – |
≥180 | – | – | 0.72 (0.41–1.27) | 0.26 | |
Study location | Multicontinental | – | – | Ref | – |
Europe | – | – | 1.89 (0.22–16.63) | 0.57 | |
US and Canada | – | – | 1.16 (0.13–10.10) | 0.90 | |
Asia and Pacific | – | – | 1.02 (0.11–9.36) | 0.98 | |
Rest of the world | – | – | 0.89 (0.06–12.55) | 0.93 | |
Pseudo-R2, % | 38.3 | 42.4 | |||
BIC | 571.3 | 666.9 |
Variable | Level | Best-Subset Model | Full Model | ||
---|---|---|---|---|---|
aOR (95% CI) | P | aOR (95% CI) | P | ||
Vaccine | Monovalent a | – | – | 1.48 (0.79–2.78) | 0.22 |
Trivalent a | – | – | 1.56 (0.90–2.70) | 0.11 | |
Quadrivalent | – | – | 1.76 (0.99–3.14) | 0.055 | |
Adjuvanted a | 1.56 (1.09–2.23) | 0.014 * | 1.53 (1.03–2.29) | 0.035 * | |
Intradermal a | – | – | 1.15 (0.58–2.27) | 0.69 | |
Live/intranasal a | 2.56 (1.65–3.96) | <0.001 *** | 2.66 (1.65–4.29) | <0.001 *** | |
Cell-derived/recombinant a | – | – | 1.35 (0.86–2.12) | 0.20 | |
Universal candidates a | 10.10 (4.17–24.19) | <.001 *** | 10.05 (4.17–24.19) | <0.001 *** | |
Age | Any | – | – | Ref | – |
Children only | – | – | 0.63 (0.27–1.48) | 0.29 | |
Adults only | – | – | 1.16 (0.55–2.47) | 0.70 | |
Elderly only | – | – | 0.92 (0.38–2.26) | 0.86 | |
Children and adults | – | – | 0.60 (0.22–1.63) | 0.32 | |
Adults and elderly | – | – | 0.83 (0.40–1.76) | 0.63 | |
Study type | Observational | – | – | Ref | – |
Interventional | – | – | 0.64 (0.35–1.17) | 0.15 | |
Study phase | 1 | Ref | – | Ref | – |
2 | 0.56 (0.37–0.87) | 0.009 ** | 0.72 (0.45–1.14) | 0.16 | |
3 | 0.32 (0.18–0.56) | <0.001 *** | 0.47 (0.25–0.90) | 0.022 * | |
4 | 0.94 (0.62–1.42) | 0.76 | 1.17 (0.70–1.95) | 0.54 | |
Industry sponsored | No | Ref | – | Ref | – |
Yes | 0.32 (0.23–0.45) | <0.001 *** | 0.31 (0.21–0.46) | <0.001 *** | |
Time | Year b | – | – | 0.99 (0.94–1.03) | 0.60 |
Sample size | <180 | – | – | Ref | – |
≥180 | – | – | 0.62 (0.44–0.88) | 0.007 ** | |
Study location | Multicontinental | – | – | Ref | – |
Europe | – | – | 3.95 (0.84–18.54) | 0.08 | |
US and Canada | – | – | 2.28 (0.49–10.68) | 0.30 | |
Asia and Pacific | – | – | 1.68 (0.35–8.14) | 0.52 | |
Rest of the world | – | – | 2.32 (0.41–13.31) | 0.34 | |
Pseudo-R2, % | 23.4 | 29.5 | |||
BIC | 1144.4 | 1224.4 |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Domnich, A.; Manini, I.; Panatto, D.; Calabrò, G.E.; Montomoli, E. Immunogenicity Measures of Influenza Vaccines: A Study of 1164 Registered Clinical Trials. Vaccines 2020, 8, 325. https://doi.org/10.3390/vaccines8020325
Domnich A, Manini I, Panatto D, Calabrò GE, Montomoli E. Immunogenicity Measures of Influenza Vaccines: A Study of 1164 Registered Clinical Trials. Vaccines. 2020; 8(2):325. https://doi.org/10.3390/vaccines8020325
Chicago/Turabian StyleDomnich, Alexander, Ilaria Manini, Donatella Panatto, Giovanna Elisa Calabrò, and Emanuele Montomoli. 2020. "Immunogenicity Measures of Influenza Vaccines: A Study of 1164 Registered Clinical Trials" Vaccines 8, no. 2: 325. https://doi.org/10.3390/vaccines8020325
APA StyleDomnich, A., Manini, I., Panatto, D., Calabrò, G. E., & Montomoli, E. (2020). Immunogenicity Measures of Influenza Vaccines: A Study of 1164 Registered Clinical Trials. Vaccines, 8(2), 325. https://doi.org/10.3390/vaccines8020325