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

Gene Tan

doi:doi:10.1162/2e3983f5.921338c5

Efficacy and Safety of NVX-CoV2373 in Adults in the United States and Mexico

by Lisa M. Dunkle, Karen L. Kotloff, Cynthia L. Gay, Germán Áñez, Jeffrey M. Adelglass, Alejandro Q. Barrat Hernández, Wayne L. Harper, Daniel M. Duncanson, Monica A. McArthur, Diana F. Florescu, R. Scott McClelland, Veronica Garcia-Fragoso, Robert A. Riesenberg, David B. Musante, David L. Fried, Beth E. Safirstein, Mark McKenzie, Robert J. Jeanfreau, Jeffrey K. Kingsley, Jeffrey A. Henderson, Dakotah C. Lane, Guillermo M. Ruíz-Palacios, Lawrence Corey, Kathleen M. Neuzil, Robert W. Coombs, Alex L. Greninger, Julia Hutter, Julie A. Ake, Katherine Smith, Wayne Woo, Iksung Cho, Gregory M. Glenn, Filip Dubovsky, and undefined undefined

Show Description
dx.doi.org

Description

AbstractBACKGROUNDVaccination using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein antigen has been effective in the prevention of coronavirus disease 2019 (Covid-19). NVX-CoV2373 is an adjuvanted, recombinant S protein nanoparticle vaccine that demonstrated clinical efficacy for prevention of Covid-19 in phase 2b/3 trials in the United Kingdom and South Africa.METHODSThis phase 3, randomized, observer-blinded, placebo-controlled trial evaluated the efficacy and safety of NVX-CoV2373 in adults ≥18 years of age in the United States and Mexico during the first quarter of 2021. Participants were randomized in a 2:1 ratio to receive two doses of NVX-CoV2373 or placebo 21 days apart. The primary end point was vaccine efficacy (VE) against reverse transcriptase-polymerase chain reaction-confirmed Covid-19 in SARS-CoV-2-naïve participants ≥7 days after the second dose administration.RESULTSOf the 29,949 participants randomized between December 27, 2020, and February 18, 2021, 29,582 (median age: 47 years, 12.6% ≥65 years) received ≥1 dose: 19,714 received vaccine and 9868 placebo. In the per-protocol population, there were 77 Covid-19 cases; 14 among vaccine and 63 among placebo recipients (VE: 90.4%, 95% confidence interval [CI] 82.9 to 94.6, P<0.001). All moderate-to-severe cases occurred in placebo recipients, yielding VE of 100% (95% CI 87.0 to 100). Most sequenced viral genomes (48/61, 78.7%) were variants of concern (VOC) or interest (VOI), mainly represented by variant alpha/B.1.1.7 (31/35, 88.6% VOC identified). VE against any VOC/VOI was 92.6% (95% CI 83.6 to 96.7). Reactogenicity was mostly mild-to-moderate and transient, but more frequent in NVX-CoV2373 recipients and after the second dose. Serious adverse events were rare and evenly distributed between treatments.CONCLUSIONSNVX-CoV2373 was well tolerated and demonstrated a high overall VE (>90%) for prevention of Covid-19, with most cases due to variant strains.(Funded by the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health; PREVENT-19 ClinicalTrials.gov number, NCT04611802.)

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.

***************************************

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.