ABSTRACT
Hadigal et al. argued the recommendation of high-dose influenza vaccine over standard-dose formulation is not supported by comparisons of numbers-needed-to-vaccinate (NNV) nor aligned with the WHO mandate of improving vaccine coverage. However, the authors’ NNV calculation was inaccurate. A preferential recommendation for vaccines preventing influenza/complications can increase coverage. Furthermore, the impact of vaccination is a function of efficacy/effectiveness and the vaccine-preventable fraction of disease burden; therefore Hadigal et al. should interpret the absolute risk reduction by vaccination within the context of overall disease burden. To address the threat of COVID-19 pandemic, authorities should implement concomitant influenza/COVID-19 vaccination to reduce the burden of cocirculation of influenza and SARS- CoV- 2 viruses and increase the coverage of proven influenza vaccines as per WHO mandate.
Dear Editor,
Adults aged ≥65 years bear disproportional burden of influenza. In this age group, high-dose influenza vaccine has been shown to afford superior efficacy against lab-confirmed influenza and associated with less complications/hospitalizations in randomized controlled/real-world settings, when compared with standard-dose formulation.1 We recently published an immunobridging trial demonstrating superior immunogenicity and similar reactogenicity of high dose quadrivalent influenza vaccine (IIV4-HD) vs. standard dose quadrivalent vaccine (IIV4-SD) in adults aged ≥60 years.2 Hadigal et al. from Viatris Inc. commented on IIV4-HD following our publication,3 and here we would like to address their viewpoints.
First, we believe the numbers-needed-to-vaccinate (NNVs) reported by Hadigal et al. for trivalent IIV3-HD vs. IIV3-SD (19 vs. 18; inferred for IIV4-HD/IIV4-SD) are inaccurate and underestimate the incremental value of IIV3-HD, due to the use of 7.2% as the background attack rate of laboratory-confirmed influenza in their calculation. This attack rate was pooled from three heterogenous studies, which were conducted in different seasons/countries compared with the pivotal trial of IIV3-HD in older adults4 (USA; 2011/12 and 2012/13). In fact, the 7.2% translates to an absolute vaccine effectiveness (VE) of 74% (1–0.01882/7.2%) for IIV3-SD in the IIV3-HD trial; this is unrealistic for individuals of any age, and even more so for older adults, in whom the VE of IIV-SD3/4 is further reduced due to immunosenescence and other factors.5
For comparison, the U.S. CDC reported an overall vaccine effectiveness of 43% in 2011/12 and 26% in 2012/13 in this age group.6,7 With IIV3-SD being the standard of care in both years, we can use the CDC reported VEs as proxies for VE of IIV3-SD. The correct background attack rates for the study years of IIV3-HD trial can now be calculated using the CDC reported VEs and the attack rate amongst the IIV3-SD recipients in the IIV-HD trial for the corresponding seasons (Table 1). Using the season-specific background attack rates in the USA, we show that IIV3-HD has a much lower NNV compared with IIV3-SD, with a delta of 86 for 2011/12 and 36 for 2012/13, respectively (Table 1). The benefits of IIV3-HD over IIV3-SD as expressed in the NNV comparisons are supported by the randomized controlled trials and real-world evidence of >34 million older adults over ten consecutive seasons1
Table 1.
Number needed to vaccinate in high-dose trivalent influenza vaccine (IIV3-HD) vs standard-dose trivalent vaccine (IIV3-SD), using season-specific attack rate in the USA.
| Season | Vaccination status | Attack rate in participants* | Background attack rate† |
Absolute risk reduction (ARR) | Number needed to vaccinate (NNV) | Delta of NNV: (IIV3-SD – IIV3-HD) |
|---|---|---|---|---|---|---|
| 2011/12 | Vaccinated with IIV3-HD | 0.00317 (23/7253) | – | 0.00700 (1.02%/0.00317) | 143 (1/0.00700) |
86 (229–143) |
| Vaccinated with IIV3-SD | 0.00580 (42/7244) | – | 0.00437 (1.02%/0.00580) | 229 (1/0.00437) |
||
| Unvaccinated | – | 1.02% (0.00580/[1–43%6) |
– | – | – | |
| 2012/13 | Vaccinated with IIV3-HD | 0.02346 (205/8737) | – | 0.01654 (4.00%/0.02346) | 60 (1/0.01654) |
36 (96–60) |
| Vaccinated with IIV3-SD | 0.02960 (259/8749) | – | 0.01040 (4.00%/0.02960) | 96 (1/0.01040) |
||
| Unvaccinated | – | 4.00% (0.02960/[1–26%7) |
– | – | – |
* Derived from Supplementary Appendix, Table S9 of IIV3-HD trial.4
Second, the authors’ assertion that preferential recommendations of IIV4-HD over other formulations are “misaligned with the WHO mandate to improve vaccine coverage” is unfounded. In its latest position paper, the WHO states that, should IIV4-HD/other newer influenza vaccines “be available and affordable to countries, they should be recommended as long as their use does not jeopardize the ability to provide influenza vaccination to other target groups.”8 Rather, the introduction of influenza vaccines with proven superior protection could potentially improve the vaccine coverage. Colleagues from the U.S. CDC reported that perceived effectiveness of influenza vaccine is positively associated with the vaccine uptake in older adults.9 A preferential recommendation for a vaccine proven to outperform the standard-dose formulation in randomized trials can strengthen the public’s perception about influenza vaccine effectiveness, which in turn improves the vaccine coverage. In Germany, IIV4-HD has been preferentially recommended over other influenza vaccines to all the 24.1 million adults aged ≥60 years; this policy was successfully implemented in the first season (2021/22), with sufficient doses of IIV4-HD delivered ahead of market utilization.
Third, the authors seem to have interpreted the absolute risk reduction (ARR) without taking into account overall disease burden. The impact of vaccination is a function of vaccine efficacy/effectiveness and the vaccine-preventable fraction of the disease burden. The author cited ARRs of 0.84% to 1.3% from COVID-19 vaccines, implying the benefits of such vaccines are not as impressive as the vaccine efficacy estimates (67% to 97%) suggested. However, given the persistence and resurgence of COVID-19 pandemic, even vaccines with ARRs of 0.84% to 1.3% can result in considerable reduction of COVID-19 cases, hospitalization, and deaths. The same principles apply for newer influenza vaccines, such as IIV4-HD.
Finally, we support the call of Hadigal et al. for continuing vaccinating against influenza during the COVID-19 pandemic. Influenza has resurged in Australia this year following the lift of border restrictions for COVID-19 pandemic, with the number of influenza notifications to date well exceeding the historical record.10 Fortunately, several influenza vaccines such as IIV4-HD can be co-administered without comprising the immunogenicity and safety.11,12 To minimize the impact of potential COVID-influenza ‘twindemic’ and to maintain/improve influenza vaccine coverage as per WHO mandate, we suggest that authorities should provide clear recommendation and necessary policy measures to reinforce the importance of influenza vaccination and the implement concomitant influenza and COVID-19 vaccination programs.
Funding Statement
The author(s) reported there is no funding associated with the work featured in this article.
Disclosure statement
All authors are full-time employees of Sanofi, a manufacturer of influenza vaccines, and may hold shares and/or stock options in the company.
References
- 1.Lee JKH, Lam GKL, Shin T, Samson SI, Greenberg DP, Chit A.. Efficacy and effectiveness of high-dose influenza vaccine in older adults by circulating strain and antigenic match: An updated systematic review and meta-analysis. Vaccine. 2021;39:1–3. doi: 10.1016/j.vaccine.2020.09.004. [DOI] [PubMed] [Google Scholar]
- 2.Pepin S, Nicolas JF, Szymanski H, Leroux-Roels I, Schaum T, Bonten M, Icardi G, Shrestha A, Tabar C. Immunogenicity and safety of a quadrivalent high-dose inactivated influenza vaccine compared with a standard-dose quadrivalent influenza vaccine in healthy people aged 60 years or older: A randomized Phase III trial. Hum Vaccin Immunother. 2021;17:5475–5486. doi: 10.1080/21645515.2021.1983387. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Hadigal S, Colombo L, Haughie S. Reply letter to “Immunogenicity and safety of a quadrivalent high-dose inactivated influenza vaccine compared with a standard-dose quadrivalent influenza vaccine in healthy people aged 60 years or older: A randomized Phase III trial”. Hum Vaccin Immunother. 2022:2085470. doi: 10.1080/21645515.2022.2085470. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.DiazGranados CA, Dunning AJ, Kimmel M, Kirby D, Treanor J, Collins A, Pollak R, Christoff J, Earl J, Landolfi V, et al. Efficacy of high-dose versus standard-dose influenza vaccine in older adults. N Engl J Med. 2014;371(7):635–645. doi: 10.1056/NEJMoa1315727. [DOI] [PubMed] [Google Scholar]
- 5.The U.S. Centers for Disease Control and Prevention (CDC) . Vaccine effectiveness: how well do flu vaccines work? 2021. https://www.cdc.gov/flu/vaccines-work/vaccineeffect.htm.
- 6.The U.S. Centers for Disease Control and Prevention (CDC) . Seasonal Influenza Vaccine Effectiveness, 2011-2012. 2018. https://www.cdc.gov/flu/vaccines-work/2011-2012.html.
- 7.The U.S. Centers for Disease Control and Prevention (CDC) . Seasonal Influenza Vaccine Effectiveness, 2012-2013. 2018. https://www.cdc.gov/flu/vaccines-work/2012-2013.html.
- 8.World Health Organization (WHO) . Vaccines against influenza: WHO position paper. Wkly Epidemiol Rec 2022;19:185–208. [Google Scholar]
- 9.Wooten KG, Wortley PM, Singleton JA, Euler GL. Perceptions matter: Beliefs about influenza vaccine and vaccination behavior among elderly white, black and Hispanic Americans. Vaccine. 2012;30:6927–6934. doi: 10.1016/j.vaccine.2012.08.036. [DOI] [PubMed] [Google Scholar]
- 10.Australian Government Department of Health . Australian influenza surveillance Report No. 05; Reporting fortnight: 23 May to 05 June 2022. 2022.
- 11.Lazarus R, Baos S, Cappel-Porter H, Carson-Stevens A, Clout M, Culliford L, Emmett SR, Garstang J, Gbadamoshi L, Hallis B, et al. Safety and immunogenicity of concomitant administration of COVID-19 vaccines (ChAdox1 or BNT162b2) with seasonal influenza vaccines in adults in the UK (ComFlucov): A multicentre, randomised, controlled, phase 4 trial. Lancet. 2021;398(10318):2277–2287. doi: 10.1016/S0140-6736(21)02329-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Izikson R, Brune D, Bolduc JS, Bourron P, Fournier M, Moore TM, Pandey A, Perez L, Sater N, Shrestha A, et al. Safety and immunogenicity of a high-dose quadrivalent influenza vaccine administered concomitantly with a third dose of the mRNA-1273 SARS-CoV-2 vaccine in adults aged ≥65 years: A phase 2, randomised, open-label study. Lancet Respir Med. 2022;10(4):392–402. doi: 10.1016/S2213-2600(21)00557-9. [DOI] [PMC free article] [PubMed] [Google Scholar]