Safety, immunogenicity, and efficacy of a COVID-19 vaccine (NVX-CoV2373) co-administered with seasonal influenza vaccines: an exploratory substudy of a randomised, observer-blinded, placebo-controlled, phase 3 trial
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Abstract
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Our take
Global vaccination against COVID-19 will continue for the remainder of 2021, overlapping with seasonal influenza vaccine administration. Provision of both vaccines in a single visit would help maximize vaccine compliance, but there have been concerns regarding the safety and efficacy of co-administered vaccines. This study, available as a preprint and thus not yet peer-reviewed, demonstrates that co-administration of vaccines for SARS-CoV-2 and influenza is both safe and effective. While further research is needed, particularly among those over 65 years of age, these data could be used to guide national vaccine policy decision making, since vaccine co-administration appears to be a viable and safe option.
Study design
randomized-controlled-trial;non-randomized-trial
Study population and setting
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Our take
Global vaccination against COVID-19 will continue for the remainder of 2021, overlapping with seasonal influenza vaccine administration. Provision of both vaccines in a single visit would help maximize vaccine compliance, but there have been concerns regarding the safety and efficacy of co-administered vaccines. This study, available as a preprint and thus not yet peer-reviewed, demonstrates that co-administration of vaccines for SARS-CoV-2 and influenza is both safe and effective. While further research is needed, particularly among those over 65 years of age, these data could be used to guide national vaccine policy decision making, since vaccine co-administration appears to be a viable and safe option.
Study design
randomized-controlled-trial;non-randomized-trial
Study population and setting
Conducted as a substudy of the phase 3 trial for NVX-CoV2373 (Novavax; September-November 2020), this study assessed the safety and efficacy of open label influenza vaccine coadministration with the first dose of NVXCoV2373 (n= 217) vs. placebo (n=214). Rates of minor vaccine reactions (collected via electronic diary) and adverse events were compared to a reactogenicity cohort from the main study (n=2000). Immunogenicity against influenza was assessed using a hemagglutination inhibitor assay, while that against SARS-CoV-2 was assessed by quantifying anti-spike IgG with ELISA; results were compared to an immunogenicity cohort from the main study (n=900). The primary vaccine efficacy endpoint was based on PCR detection of symptomatic SARS-CoV-2 infection at least seven days after administration of the second vaccine dose in participants aged 18 to 64 years who had not been previously infected with SARS-CoV-2 (n=360). Results were compared to vaccine efficacy for the per-protocol population of the main study age 18 to 64 years (n= 10,129), as well as vaccine efficacy against the Alpha variant for the per-protocol population of the main study (n=14,040).
Summary of main findings
Participants who received both vaccines had an increased frequency of minor reactions, including pain at the injection site, muscle aches, and fatigue. True adverse events were infrequent and not associated with vaccine co-administration. There was no significant change in the immune response to the influenza vaccine as a function of co-administration. However, antibody responses generated to NVX-CoV2373 were reduced among participants who had received both vaccines, as compared to those who had received only NVX-CoV2373. Vaccine efficacy in the co-administration substudy was 87.5% (CI: -0.2 – 98.4%), as compared to 89.8% (95% CI: 79.7 – 95.5%) for the main study. All substudy breakthrough infections were due to the Alpha variant; vaccine efficacy in the main study against the Alpha variant was 86.3% (95% CI: 71.3 – 93.5%).
Study strengths
This study employed a placebo-controlled design to assess the safety and efficacy of coadministration of vaccines for SARS-CoV-2 and influenza. Influenza vaccines were assigned based on the public health guidelines for each age group. The study included laboratory measures of immunogenicity, as well as vaccine efficacy based on breakthrough infection events.
Limitations
Participation in the co-administration substudy, the reactogenicity cohort, and the immunogenicity cohort was not randomized. Substudy participants were younger, more diverse, and had fewer comorbidities than those in the main study. Influenza vaccine was administered open label to allow participants to discriminate between vaccine sites for reaction documentation. NVX-CoV2373 immunogenicity was assessed based on total antibody titer to spike protein, not neutralizing antibody titer. Due to the small number of substudy endpoint cases, 95% confidence intervals for NVX-CoV2373 efficacy were quite broad and the lower bound contained zero. The small number of breakthrough infection events also prevented the assessment of co-administered vaccine efficacy in individuals age 65 or older.
Value added
This is the first study demonstrating the safety and efficacy of coadministration of vaccines for SARS-CoV-2 and influenza.
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SciScore for 10.1101/2021.06.09.21258556: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: All participants provided written informed consent before enrolment in the trial.
IRB: The trial protocol was approved by the North West—Greater Manchester Central Research Ethics Committee (Ref 20/NW/03/99) and was performed in accordance with the International Council for Harmonisation Good Clinical Practice guidelines.Sex as a biological variable Eligible participants for the main trial were men and non-pregnant women 18 to 84 years of age (inclusive) who were healthy or had stable chronic medical conditions. Randomization Sub-study enrolment was not randomized or stratified by age. Blinding not detected. Power Analysis The target number of 100 cases for the final analysis provides >95%… SciScore for 10.1101/2021.06.09.21258556: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: All participants provided written informed consent before enrolment in the trial.
IRB: The trial protocol was approved by the North West—Greater Manchester Central Research Ethics Committee (Ref 20/NW/03/99) and was performed in accordance with the International Council for Harmonisation Good Clinical Practice guidelines.Sex as a biological variable Eligible participants for the main trial were men and non-pregnant women 18 to 84 years of age (inclusive) who were healthy or had stable chronic medical conditions. Randomization Sub-study enrolment was not randomized or stratified by age. Blinding not detected. Power Analysis The target number of 100 cases for the final analysis provides >95% power for 70% or higher vaccine efficacy. Table 2: Resources
Antibodies Sentences Resources For the SARS-CoV-2 anti-S protein IgG antibody levels measured by the ELISA assay, geometric mean ELISA units (GMEUs) at each study visit (Day 0 and Day 35), the geometric mean fold rises (GMFRs) comparing at Day 0 and at Day 35, along with 95% CI, were summarised by vaccine group (NVX-CoV2373 plus influenza vaccine; NVX-CoV2373 alone; placebo plus influenza vaccine; placebo alone). anti-S protein IgGsuggested: NoneFor both HAI and IgG antibody measured by treatment group, the 95% CIs were calculated based on the t distribution of the log-transformed values, then back transformed to the original scale for presentation as GMTs/GMEUs and GMFRs. IgGsuggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Study limitations include the small overall sub-study size (with few participants ≥65 years of age owing to the high rate of routine influenza vaccination among participants in this age group at study start), small number of sub-study efficacy endpoints, lack of formal pre-specified non-inferiority statistical assessment of immunogenicity, and the lack of randomization in recruiting the influenza sub-study, immunogenicity, and reactogenicity cohorts. A stronger design could have been four randomized arms consisting of NVX-CoV2373 plus influenza vaccine, NVX-CoV2373 plus placebo, influenza vaccine plus placebo, and placebo plus placebo. Another limitation was the open-label design in administering the influenza vaccine, but this was required to order to allow participants to consider only the study vaccine injection site for assessment of local symptoms. Finally, the assessment of neutralising antibody titres may have benefitted the immunogenicity investigation, yet prior studies with NVX-CoV2373 have shown a strong correlation between the anti-S and wild-type microneutralizations results.18 This is the first study to demonstrate the safety, immunogenicity, and efficacy profile of a COVID-19 vaccine when co-administered with a seasonal influenza vaccine. These data demonstrate no early safety concerns with the concomitant administration of NVX-CoV2373 with an influenza vaccine. Immunogenicity of the influenza vaccine was preserved with concomitant administration while a modest...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04583995 Recruiting A Study Looking at the Effectiveness, Immune Response, and S… Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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