Safety and Immunogenicity of the BNT162b2 Vaccine Coadministered with Seasonal Inactivated Influenza Vaccine in Adults

Widespread use of safe and effective vaccines has been critical to curtailing the COVID-19 pandemic. The efficacy and safety of two doses of the BNT162b2 mRNA COVID-19 vaccine was established in a global phase 2/3 trial in those 16 years and older, with vaccine efficacy of 95.0% [1]. In a phase 3 study, the efficacy of a third BNT162b2 dose given ≥ 6 months after the last previous dose was 95.3% among those 16 years and older, and reduced rates of SARS-CoV-2 infection and severe COVID-19 among older adults who had received their last dose at least 5 months prior [2, 3]. Effectiveness of COVID-19 vaccine booster doses against milder disease wanes over months, but remains high against severe disease and mortality when the vaccine is more closely matched to circulating SARS-CoV-2 variants [4‐7]. Data also indicate that COVID-19 displays seasonal epidemiologic patterns, predominating in the winter season [8, 9]. Many countries currently recommend seasonal COVID-19 vaccine boosters to address future disease waves and the emergence of highly transmissible and potentially virulent strains [10‐14].

Influenza is another seasonal respiratory disease that causes yearly epidemics, and occasionally pandemics, and is associated with substantial morbidity and mortality, particularly among older adults, very young children, those who are pregnant, and those with certain chronic medical conditions [15, 16]. In temperate regions, influenza transmission occurs predominantly in the winter season.

As the COVID-19 pandemic abates and seasonality of viral respiratory disease returns to more typical patterns, there is a risk that peaks of influenza, COVID-19, and respiratory syncytial virus illnesses will occur, particularly in winter, straining healthcare resources [17]. Although with an estimated prevalence of < 1% [18], coinfection with SARS-CoV-2 and the influenza virus may also occur [19], which could lead to adverse outcomes [17, 19‐21]. Together, these prospects reinforce the importance of vaccination against both COVID-19 and influenza.

Seasonal vaccination against influenza represents the primary strategy for preventing influenza illness and its complications [16]. Effectiveness of influenza vaccination is dependent on several factors, including the similarity between circulating influenza viruses and the virus strains covered by the seasonal vaccine. Accordingly, annual influenza vaccine updates are necessitated by the typical peak of illness in winter months and the constant evolution of the influenza virus, to support vaccines more closely matched to circulating strains [22]. Adult annual seasonal influenza vaccination is recommended in many countries, particularly for individuals with risk factors for increased influenza morbidity and mortality, such as older adults and those with chronic medical conditions [16, 23, 24].

Because recommendations for COVID-19 vaccination and influenza vaccination have considerable overlap, including recommended age groups, at-risk populations, and timing, both vaccines may need to be administered at the same time. Such guidance is already provided in some jurisdictions, including the USA and European Union, and by the World Health Organization (WHO) [10, 24‐27]. This is based on the principle that two inactivated vaccines can be given concurrently and with the aim of maximizing the opportunity to receive both vaccines, and eliminating the need for more than one healthcare visit for those receiving both vaccines, which will be more convenient for the healthcare provider and the vaccine recipient and may lead to improved vaccination rates.

To investigate the coadministration of BNT162b2 and seasonal inactivated influenza vaccine (SIIV) in adult populations, this study assessed the safety, tolerability, and immunogenicity of a fourth dose (booster) of BNT162b2 administered either concomitantly with SIIV or separately 1 month after SIIV in adults who had received three previous doses of BNT162b2.

Vaccination is a critical approach to protect against the severe outcomes of both COVID-19 and influenza, both of which are associated with substantial morbidity and mortality particularly in vulnerable populations [15, 16, 28‐30]. However, vaccination rates for both COVID-19 and influenza vaccines in many regions are suboptimal [29]. Coadministration of these vaccines, which is currently recommended in several countries and by the WHO [10, 24‐26], may potentially improve vaccine uptake, and accordingly, vaccination rates, and may therefore maximize protection during peak disease periods and improve the resilience of healthcare systems [28, 29, 31, 32]. Support for this approach as a means to improve vaccination rates comes from an assessment of the 2021 Australian concurrent influenza and COVID-19 vaccination programs [33]. At the time, sequential administration of COVID-19 vaccines with other vaccinations was recommended. However, a substantial decrease in influenza vaccination rates was noted (i.e., 68% by June 2021 compared with 80% in 2020 and 74% in 2019), suggesting that sequential administration may have contributed to decreased influenza vaccination rates.

In this phase 3 study, we observed robust immune responses regardless of concomitant or separate administration of BNT162b2 and SIIV. The immune responses with coadministration of the BNT162b2 COVID-19 vaccine and SIIV were noninferior to the immune responses elicited by either vaccine alone, meeting the prespecified noninferiority criterion for both vaccines. Coadministration of BNT162b2 with SIIV was safe and well tolerated, with an overall safety profile similar to BNT162b2 administered alone. Together, these results provide support for coadministration of BNT162b2 and SIIV.

Determining whether coadministration of COVID-19 and influenza vaccines leads to immune interference is an important consideration when implementing coadministration vaccination strategies [19, 31, 34]. Results from prospective studies assessing coadministration of COVID-19 vaccine booster doses with an influenza vaccine describing the effect on immune responses are available [35‐39]. To our knowledge, only one other study has provided a statistical assessment of the noninferiority of the immune response of coadministration of a COVID-19 vaccine and an influenza vaccine compared with separate administration [38]. In that randomized study, immunogenicity of coadministration of a BNT162b2 booster with an influenza vaccine was compared with BNT162b2 alone in 154 participants 60 years and older who were fully vaccinated with any COVID-19 vaccine [38]. That study failed to confirm the noninferiority of concurrent administration compared with administration of BNT162b2 alone, and both the levels and functionality of the immune response against SARS-CoV-2 were decreased with coadministration, suggesting possible immune interference as a result of coadministration. A key limitation of that study was the heterogeneous history of prior COVID-19 vaccinations across vaccine platforms (viral vectored, mRNA) that likely contributed to more variable baseline immunity that could impact the ability to achieve noninferiority with subsequent coadministration of COVID-19 vaccine with a seasonal influenza vaccine.

The tolerability or safety profile of either vaccine is another important consideration in assessing coadministration approaches [31]. Prospective studies have shown that tolerability and safety profiles do not appear to be adversely affected with coadministration of a COVID-19 vaccine with influenza vaccine [35‐39]. In a phase 4 study that included 679 participants who were randomized to receive a second dose of BNT162b2 or the ChAdOx1 adenovirus COVID-19 vaccine, at the same time as one of three different influenza vaccines, no safety concerns with coadministration were identified [35]. Support for the safety of coadministration of mRNA COVID-19 vaccines with SIIV is also available from an analysis of data from the US Vaccine Adverse Event Reporting System (VAERS) safety surveillance program [40]. The analysis of data from July 2021 to June 2022 concluded that no new or unexpected safety issues were identified, and the safety profile of coadministration was generally consistent with the safety profile of either vaccine given alone. Additionally, a surveillance study from the US Centers for Disease Control and Prevention (CDC) found that systemic events occurred 8–11% more frequently in individuals who received mRNA COVID-19 vaccine booster doses with seasonal influenza vaccination (n = 92,023) than in those who received the COVID-19 vaccine booster alone (n = 889,076) [41]. However, events reported in that surveillance study were usually mild. Finally, a preliminary potential ischemic stroke signal was identified by the CDC for the Omicron BA.4/BA.5 variant-adapted bivalent BNT162b2 vaccine among older adults [42]. However, further analyses of the Omicron BA.1 variant-adapted bivalent BNT162b2 vaccine given alone or given on the same day as influenza vaccination identified no increased risk of ischemic or hemorrhagic stroke, including among older adults [43]. With the accumulation of further safety data, the initial CDC finding has decreased and it is thought that factors other than vaccination contributed to this preliminary finding [42], and the CDC continues to recommend coadministration of COVID-19 vaccines with influenza vaccines [44]. Additionally, we saw no stroke events in our study, which used the original BNT162b2 vaccine.

Strengths of our study include the randomized design and the assessment of noninferiority of the immune response of coadministration of BNT162b2 and SIIV compared with separate administration of either vaccine, while allowing all participants to receive both vaccines. Limitations of our study should also be noted. The study was conducted in Australia and New Zealand in 18- to 64-year-old adults who had received three prior doses of BNT162b2; however, we anticipate that the findings will be generalizable to other adult populations, such as the elderly, and across geographic regions and among individuals who may have received other COVID-19 vaccines for their primary series. The follow-up for safety was also limited to 1 month after each vaccination. The primary BNT162b2 immunogenicity endpoint of our study was assessment of full-length S-binding IgG levels. It is anticipated that subsequent analysis of SARS-CoV-2 neutralizing titers will be supportive of the findings of the primary analysis because trends for S-binding IgG and neutralizing responses have been generally similar following COVID-19 vaccination. Notably, the only other study powered to assess noninferiority of coadministration of a COVID-19 vaccine and influenza vaccine compared with COVID-19 booster vaccination alone also assessed IgG responses [38]. Additionally, Omicron-adapted vaccines are now being used in several countries, including Australia, New Zealand, and the USA [10, 11, 45]. However, we anticipate that the findings reported here for original BNT162b2 will be generalizable to the variant-adapted vaccines, and regulators are not generally requiring further clinical data with every update to the COVID-19 mRNA vaccine platform, nor with every seasonal update to SIIVs [46, 47]. Finally, the effectiveness of coadministration vaccination strategies to protect against COVID-19 and influenza illness remains to be determined, and such confirmation would require real-world studies.

In conclusion, this study demonstrated that BNT162b2 can be administered concomitantly with SIIV in adults 18–64 years of age. BNT162b2 was safe and well tolerated when coadministered with SIIV and showed robust immune responses that were noninferior to separate administration of BNT162b2 and SIIV. Acceptance of influenza vaccine and COVID-19 vaccine coadministration is an important consideration, with studies reporting low public acceptance of this approach, particularly attributed to concerns regarding decreased effectiveness and increased adverse reactions with coadministration [31]. The rigorous clinical trial data reported here supporting the coadministration of these vaccines should help to assuage these concerns.