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PreprintCited by 625SARS-CoV-2 and COVID-19 ResearchCOVID-19 Clinical Research StudiesAnimal Virus Infections Studies

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Preliminary Efficacy of the NVX-CoV2373 Covid-19 Vaccine Against the B.1.351 Variant

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Shinde, Vivek, Bhikha, Sutika, Hoosain, Zaheer, Archary, Moherndran, Bhorat, Qasim, Fairlie, Lee, Lalloo, Umesh, Masilela, Mduduzi S. L., Moodley, Dhayendre, Hanley, Sherika, Fouche, Leon, Louw, Cheryl, Tameris, Michele, Singh, Nishanta, Goga, Ameena, Dheda, Keertan, Grobbelaar, Coert, Kruger, Gertruida, Carrim-Ganey, Nazira, Baillie, Vicky, de Oliveira, Tulio, Koen, Anthonet Lombard, Lombaard, Johan J., Mngqibisa, Rosie, Bhorat, As’ad Ebrahim, Benadé, Gabriella, Lalloo, Natasha, Pitsi, Annah, Vollgraaff, Pieter-Louis, Luabeya, Angelique, Esmail, Aliasgar, Petrick, Friedrich G., Jose, Aylin Oommen, Foulkes, Sharne, Ahmed, Khatija, Thombrayil, Asha, Fries, Lou, Cloney-Clark, Shane, Zhu, Mingzhu, Bennett, Chijioke, Albert, Gary, Faust, Emmanuel, Plested, Joyce S., Robertson, Andreana, Neal, Susan, Cho, Iksung, Glenn, Greg M., Dubovsky, Filip, Madhi, Shabir A., for the 2019nCoV-501 Study Group·2021·New England Journal of Medicine
DOI 10.1101/2021.02.25.21252477PMC PMC8091623

Preprint — published as 10.1056/nejmoa2103055 · Paper page

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Abstract

Background: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the Covid-19 pandemic. Evaluation of Covid-19 vaccine efficacy against SARS-CoV-2 variants is urgently needed to inform vaccine development and use. Methods: In this phase 2a/b, multicenter, randomized, observer-blinded, placebo-controlled trial in South Africa, healthy human immunodeficiency virus (HIV)-negative adults (18 to 84 years) or medically stable people living with HIV (PLWH) (18 to 84 years) were randomized in a 1:1 ratio to receive two doses, administered 21 days apart, of either NVX-CoV2373 nanoparticle vaccine (5 µg recombinant spike protein with 50 µg Matrix-M1 adjuvant) or placebo. The primary endpoints were safety and vaccine efficacy ≥7 days following the second dose against laboratory-confirmed symptomatic Covid-19 in previously SARS-CoV-2 uninfected participants. Results: A total of 4387 participants were randomized and dosed at least once, 2199 with NVX-CoV2373 and 2188 with placebo. Approximately 30% of participants were seropositive at baseline. Among 2684 baseline seronegative participants (94% HIV-negative; 6% PLWH), there were 15 and 29 predominantly mild to moderate Covid-19 cases in NVX-CoV2373 and placebo recipients, respectively; vaccine efficacy was 49.4% (95% confidence interval [CI]: 6.1 to 72.8). Efficacy in HIV-negative participants was 60.1% (95% CI: 19.9 to 80.1), and did not differ by baseline serostatus. Of the primary endpoint cases with available whole genome sequencing, 38 (92.7%) of 41 were the B.1.351 variant. Post-hoc vaccine efficacy against B.1.351 was 51.0% (95% CI: - 0.6 to 76.2) in HIV-negative participants. Among placebo recipients, the incidence of symptomatic Covid-19 was similar in baseline seronegative vs baseline seropositive participants during the first 2 months of follow-up (5.3% vs 5.2%). Preliminary local and systemic reactogenicity were primarily mild to moderate and transient, and higher with NVX-CoV2373; serious adverse events were rare in both groups. Conclusions: The NVX-CoV2373 vaccine was efficacious in preventing Covid-19, which was predominantly mild to moderate and due to the B.1.351 variant, while evidence of prior infection with the presumptive original SARS-CoV-2 did not confer protection against probable B.1.351 disease. (Funded by Novavax, The Bill and Melinda Gates Foundation, and the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number, NCT04533399 )

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Figure 1. Disposition of Participants in the Trial. The full analysis set included all participants who were randomly assigned to treatment and received at least one dose, regardless of protocol violations or missing data, and are analyzed according to the trial vaccine group as randomized. This diagram represents the disposition of participants in the trial. Among participants excluded for not meeting inclusion/exclusion criteria: approximately 32% tested HIV-positive on screening, 18% had a history of suspected or diagnosed Covid-19, 11% had an exclusionary chronic disease condition, 9% had exclusionary high or low BMI, 7% could not provide informed consent, and 5% had acute or ongoing illness. Among participants excluded for “other” reasons: approximately 69% were otherwise eligible but had missed the time window for enrollment into a particular stage or cohort; and 23% of “other” did not meet inclusion/exclusion criteria but were recorded under the free text category of “other” (these had a similar distribution of exclusion criteria as those recorded under “not meeting inclusion/exclusion criteria”). The data cutoff date for the primary efficacy analysis was January 8, 2021, which represented a median follow-up of 66 and 45 days after first and second vaccination, respectively. The data cutoff date for the primary safety analysis was January 25, 2021, which included safety data through 35 days after first vaccination in all 968 Stage 1 participants (889 HIV-negative and 79 PLWH). The safety analysis set included all participants who received at least one dose of NVX-CoV2373 or placebo, with participants analyzed according to the treatment actually received. The per-protocol efficacy analysis set (PP-EFF) included baseline seronegative (by anti-spike IgG) participants who received both injection of NVX-CoV2373 or placebo as assigned, had no evidence of SARS-CoV-2 infection (by NAAT or anti-spike IgG) within 7 days after the second vaccination (ie, before Day 28), and had no major protocol deviations affecting the primary efficacy outcome. A second per-protocol efficacy analysis set (PP-EFF-2) was defined in a similar fashion except without the exclusion of baseline seropositive participants to allow for analysis of efficacy in seropositive or all participants, regardless of serostatus. Abbreviations: HIV = human immunodeficiency virus; IgG = immunoglobulin G; NAAT = nucleic acid amplification test; PLWH = people living with HIV; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
Figure 1. Disposition of Participants in the Trial. The full analysis set included all participants who were randomly assigned to treatment and received at least one dose, regardless of protocol violations or missing data, and are analyzed according to the trial vaccine group as randomized. This diagram represents the disposition of participants in the trial. Among participants excluded for not meeting inclusion/exclusion criteria: approximately 32% tested HIV-positive on screening, 18% had a history of suspected or diagnosed Covid-19, 11% had an exclusionary chronic disease condition, 9% had exclusionary high or low BMI, 7% could not provide informed consent, and 5% had acute or ongoing illness. Among participants excluded for “other” reasons: approximately 69% were otherwise eligible but had missed the time window for enrollment into a particular stage or cohort; and 23% of “other” did not meet inclusion/exclusion criteria but were recorded under the free text category of “other” (these had a similar distribution of exclusion criteria as those recorded under “not meeting inclusion/exclusion criteria”). The data cutoff date for the primary efficacy analysis was January 8, 2021, which represented a median follow-up of 66 and 45 days after first and second vaccination, respectively. The data cutoff date for the primary safety analysis was January 25, 2021, which included safety data through 35 days after first vaccination in all 968 Stage 1 participants (889 HIV-negative and 79 PLWH). The safety analysis set included all participants who received at least one dose of NVX-CoV2373 or placebo, with participants analyzed according to the treatment actually received. The per-protocol efficacy analysis set (PP-EFF) included baseline seronegative (by anti-spike IgG) participants who received both injection of NVX-CoV2373 or placebo as assigned, had no evidence of SARS-CoV-2 infection (by NAAT or anti-spike IgG) within 7 days after the second vaccination (ie, before Day 28), and had no major protocol deviations affecting the primary efficacy outcome. A second per-protocol efficacy analysis set (PP-EFF-2) was defined in a similar fashion except without the exclusion of baseline seropositive participants to allow for analysis of efficacy in seropositive or all participants, regardless of serostatus. Abbreviations: HIV = human immunodeficiency virus; IgG = immunoglobulin G; NAAT = nucleic acid amplification test; PLWH = people living with HIV; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.CC BY · PubMed Central
Figure 2. Kaplan-Meyer Plots of Efficacy of NVX-CoV2373 Against Symptomatic Covid-19, Risk of Symptomatic Covid-19 in Seropositive versus Seronegative Placebo Recipients, and Timing of Endpoint Accrual. Shown is the cumulative incidence of symptomatic Covid-19. The time period for surveillance of per-protocol symptomatic Covid-19 cases was from at least 7 days after the second dose (ie, Day 28) of NVX-CoV2373 or placebo through the first 2 months of follow-up. Data shown are for the per-protocol efficacy analysis sets (PP-EFF or PP-EFF-2), unless otherwise indicated. A) All participants (HIV-negative and PLWH), baseline seronegative; B) HIV-negative participants, baseline seronegative; C) Placebo participants, baseline seronegative vs baseline seropositive, in the full analysis set (FAS) from Day 0 onwards. The FAS included all participants who were randomly assigned to treatment and receive at least 1 dose, regardless of protocol violations or missing data. D) Per protocol efficacy endpoint accrual relative to distribution of variant as reported in Nextstrain.org. A. All participants (baseline seronegative): primary efficacy endpoint from 7 days after second dose (Day 28) in the per-protocol analysis set B. HIV-negative participants (baseline seronegative): primary efficacy endpoint from 7 days after second dose (Day 28) in the per-protocol analysis set C. Placebo participants ONLY (baseline seronegative placebo versus baseline seropositive placebo): primary efficacy endpoint from Day 0 onwards in the full analysis set D. Accrual of Primary Efficacy Endpoints Relative to B.1.351 (501Y.V2) Variant Circulation in South Africa by Time. Source: Nextstrain.org. Freely available under the terms of the GNU Affero General Public License.
Figure 2. Kaplan-Meyer Plots of Efficacy of NVX-CoV2373 Against Symptomatic Covid-19, Risk of Symptomatic Covid-19 in Seropositive versus Seronegative Placebo Recipients, and Timing of Endpoint Accrual. Shown is the cumulative incidence of symptomatic Covid-19. The time period for surveillance of per-protocol symptomatic Covid-19 cases was from at least 7 days after the second dose (ie, Day 28) of NVX-CoV2373 or placebo through the first 2 months of follow-up. Data shown are for the per-protocol efficacy analysis sets (PP-EFF or PP-EFF-2), unless otherwise indicated. A) All participants (HIV-negative and PLWH), baseline seronegative; B) HIV-negative participants, baseline seronegative; C) Placebo participants, baseline seronegative vs baseline seropositive, in the full analysis set (FAS) from Day 0 onwards. The FAS included all participants who were randomly assigned to treatment and receive at least 1 dose, regardless of protocol violations or missing data. D) Per protocol efficacy endpoint accrual relative to distribution of variant as reported in Nextstrain.org. A. All participants (baseline seronegative): primary efficacy endpoint from 7 days after second dose (Day 28) in the per-protocol analysis set B. HIV-negative participants (baseline seronegative): primary efficacy endpoint from 7 days after second dose (Day 28) in the per-protocol analysis set C. Placebo participants ONLY (baseline seronegative placebo versus baseline seropositive placebo): primary efficacy endpoint from Day 0 onwards in the full analysis set D. Accrual of Primary Efficacy Endpoints Relative to B.1.351 (501Y.V2) Variant Circulation in South Africa by Time. Source: Nextstrain.org. Freely available under the terms of the GNU Affero General Public License.CC BY · PubMed Central

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  1. 2004, A modified poisson regression approach to prospective studies with binary data Am J Epidemiol, 159, 702

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Metadata

Authors
Shinde, V., Bhikha, S., Hoosain, Z., Archary, M., Bhorat, Q., Fairlie, L., Lalloo, U., Masilela, M. S. L., Moodley, D., Hanley, S., Fouche, L., Louw, C., Tameris, M., Singh, N., Goga, A., Dheda, K., Grobbelaar, C., Kruger, G., Carrim-Ganey, N., Baillie, V., de Oliveira, T., Koen, A. L., Lombaard, J. J., Mngqibisa, R., Bhorat, A. E., Benadé, G., Lalloo, N., Pitsi, A., Vollgraaff, P.-L., Luabeya, A., Esmail, A., Petrick, F. G., Jose, A. O., Foulkes, S., Ahmed, K., Thombrayil, A., Fries, L., Cloney-Clark, S., Zhu, M., Bennett, C., Albert, G., Faust, E., Plested, J. S., Robertson, A., Neal, S., Cho, I., Glenn, G. M., Dubovsky, F., Madhi, S. A., & for the 2019nCoV-501 Study Group
Affiliations
  • Novavax (United States) (US)
  • South African Medical Research Council (ZA)
  • University of the Free State (ZA)
  • University of KwaZulu-Natal (ZA)
  • University of the Witwatersrand (ZA)
  • Setshaba Research Centre (ZA)
  • Centre for the AIDS Programme of Research in South Africa (ZA)
  • University of Pretoria (ZA)
  • University of Cape Town (ZA)
  • Clinical Trial Center Maastricht (NL)
Corresponding author
Shinde, Vivek
ORCID
Venue
New England Journal of Medicine
Publisher
openRxiv
Published
2021-03-03
Volume
384
Issue
20
Pages
1899-1909
ISSN
0028-4793 (ISSN-L)
DOI
10.1101/2021.02.25.21252477
PMC
PMC8091623
OpenAlex
W3157709232
Cited by
625
References
19
Citations by year
2026: 10 · 2025: 19 · 2024: 46 · 2023: 97 · 2022: 229 · 2021: 221
FWCI
47.03
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • New England Journal of Medicine (publishedVersion, cc-by)
  • medRxiv (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by)
  • LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
  • UpSpace Institutional Repository (University of Pretoria) (submittedVersion)
Funders
  • Pfizer
  • Sanofi
  • Regeneron Pharmaceuticals
  • Novavax
  • Novo Nordisk
  • National Institute of Allergy and Infectious Diseases (UM1AI069469)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
Keywords
NVX-CoV2373, COVID-19 vaccines, vaccine efficacy, nanoparticle vaccine, HIV-infected adults, HIV-negative individuals, neutralizing antibodies, CD4+ T cell responses, reactogenicity, South Africa, Omicron variant
MeSH terms
Immunogenicity, Vaccine, COVID-19, SARS-CoV-2, COVID-19 Vaccines, COVID-19 Serological Testing, Adolescent, Adult, Aged, Aged, 80 and over, Double-Blind Method, HIV Seropositivity, Humans, Middle Aged, South Africa, HIV Seronegativity, Young Adult, Antibodies, Neutralizing

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