Safety and immunogenicity of four sequential doses of NVX-CoV2373 in adults and adolescents: a phase 3, randomized, placebo-controlled trial (PREVENT-19)

BackgroundNVX-CoV2373, a recombinant SARS-CoV-2 spike (rS) protein vaccine with Matrix-M adjuvant, has been authorized for use in adults and adolescents. PREVENT-19 (NCT04611802/2019nCoV-301), a pivotal phase 3, randomized, placebo-controlled trial demonstrated robust efficacy of a primary, 2-dose series of NVX-CoV2373 against COVID-19. MethodsProtocol expansions to PREVENT-19 included enrollment of adolescents (aged 12 to <18 years) and administration of 3rd and 4th doses of NVX-CoV2373 to adults and adolescents. Participants randomized 2:1 received NVX-CoV2373 or placebo 21 days apart; 3rd and 4th doses were administered [&ge;]6 months after the preceding dose. Secondary and additional assessments included post-3rd- and 4th-dose immune responses (neutralizing antibody [nAb], anti-rS IgG, human angiotensin-converting enzyme-2-receptor binding inhibition [hACE2-RBI]) and response durability (post-3rd dose) to ancestral virus; cross-reactivity to Omicron subvariants; safety; and reactogenicity. ResultsImmune responses were observed against ancestral virus after two doses of NVX-CoV2373 but not after placebo. In both adults and adolescents, additional doses of NVX-CoV2373 increased nAb titers, anti-rS IgG levels, and hACE2-RBI; durable responses were recorded 8 months post 3rd dose. nAb responses post 3rd dose were noninferior to those post primary series. Cross-reactivity to BA.5 and BQ.1.1 variants was also observed, with anti-rS IgG levels post 3rd or 4th dose exceeding previously reported correlates of protection. Additional doses of NVX-CoV2373 were well tolerated, with no new safety signals. ConclusionsNVX-CoV2373 elicited robust and durable humoral immune responses to ancestral SARS-CoV-2 as a 3rd and 4th dose after the primary series in adults and adolescents. Cross-reactivity to relevant variants provides insight into potential protection against antigenically related, but shifted, viral strains. Additional doses of NVX-CoV2373 were well tolerated with no new safety signals. These results support the utility of this vaccine platform and continued updates, based on currently circulating strains, to help effectively combat SARS-CoV-2 infection. HighlightsO_LINVX-CoV2373 elicits robust and durable humoral immune responses to SARS-CoV-2 C_LIO_LI3rd and 4th subsequent homologous doses are immunogenic and well tolerated C_LIO_LINVX-CoV2373 was cross-reactive to variants circulating at the time of this study C_LI