Review 1: "Efficacy and Safety of NVX-CoV2373 in Adults in the United States and Mexico"

RR:C19 Evidence Scale rating by reviewer:

• Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

Dunkle and colleagues summarize a randomized, observer-blinded phase 3 trial of the Novavax recombinant S-based vaccine adjuvanted with Matrix-M (NVX-CoV2373). The study was conducted in 113 clinical sites in the United States and six in Mexico. 29,582 participants received at least one of two doses of NVX-CoV2373 21 days apart (19,714) or were given a placebo (9,868). This phase 3 study is similar to another trial conducted in the United Kingdom (UK), which has already been published (PMID 34192426). The data presented supports the claim that NVX-CoV2373 is well tolerated and results in high efficacy against moderate to severe disease. However, one group with a notable lower efficacy was found in the Hispanic/Latino group, which requires attention as this was not seen in other comparable phase-3 studies. Albeit, the other studies used a different vaccine. 

Human cohort. In contrast to the UK phase 3 trial, the present study is relatively more diverse. It has a sizeable number of participants who identify as Hispanic/Latino (21.5%), Black/African American (11.0%), and Naïve American/Alaska Native (6.2%). Notably absent are individuals that identify as Asian/Pacific Islander. Lastly, 11.8% of the participants were 65 years of age or older. Of note, this US/Mexico cohort is comparable in its ratio of Hispanic/Latino and Black/African American participants to another phase 3 trial that evaluated the efficacy of the Moderna mRNA vaccine (PMID 34379915). 

Efficacy. Overall efficacy for this study is 90.4%, which is close to the 89.7% vaccine efficacy calculated in the UK study. Based on two separate studies, since the overall vaccine efficacy is similar, there should be high confidence that these values are an accurate assessment of the overall efficacy of this vaccine. Of note, vaccine efficacy for Hispanics/Latinos was notably lower, not observed in the Moderna mRNA vaccine study. The disparity should be further investigated. Lastly, since these studies were conducted during the emergence of various variants of concerns, it can be argued that a vaccine spike based on the original Wuhan strain can still provide a good breadth of protection. Whether or not this is due to the robustness of the antibody response remains to be further investigated.  

Reactogenicity. Adverse reactions were more pronounced after the second dose, as seen in other prime-boost immunization schedules. However, based on the data shown, it can be argued that the percentage of participants who received the NVX-CoV2373 exhibiting local or systemic adverse events is slightly lower than those who received the Moderna mRNA vaccine.