With the emergence of Omicron variants, which carry several immune escape-related mutations in the spike protein, the effectiveness of COVID-19 prototype vaccines was weakened.1Cao Y Wang J Jian F et al.Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies.Nature. 2022; 602: 657-663Crossref PubMed Scopus (1072) Google Scholar, 2Sritipsukho P Khawcharoenporn T Siribumrungwong B et al.Real-life effectiveness of COVID-19 vaccine during the Omicron variant-dominant pandemic: how many booster doses do we need?.Emerg Microbes Infect. 2023; 12: 2174779Crossref PubMed Scopus (7) Google Scholar To overcome such weakness, several strategies have been adopted to update vaccines for the new SARS-CoV-2 variants, including updated mRNA vaccines (mRNA-1273.214 and CS-2034) and recombinant protein vaccine (V-01), which can induce higher immune response against Omicron variants than prototype vaccines.3Chalkias S Harper C Vrbicky K et al.A bivalent Omicron-containing booster vaccine against Covid-19.N Engl J Med. 2022; 387: 1279-1291Crossref PubMed Scopus (309) Google Scholar, 4Wu JD Li JX Liu J et al.Safety, immunogenicity, and efficacy of the mRNA vaccine CS-2034 as a heterologous booster versus homologous booster with BBIBP-CorV in adults aged ≥18 years: a randomised, double-blind, phase 2b trial.Lancet Infect Dis. 2023; 23: 1020-1030Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 5Wang XY Mahmood SF Jin F et al.Efficacy of heterologous boosting against SARS-CoV-2 using a recombinant interferon-armed fusion protein vaccine (V-01): a randomized, double-blind and placebo-controlled phase III trial.Emerg Microbes Infect. 2022; 11: 1910-1919Crossref PubMed Scopus (21) Google Scholar In this issue of The Lancet Infectious Diseases, Chijioke Bennett and colleagues6Bennett C Woo W Bloch M et al.Immunogenicity and safety of a bivalent (omicron BA.5 plus ancestral) SARS-CoV-2 recombinant spike protein vaccine as a heterologous booster dose: interim analysis of a phase 3, non-inferiority, randomised, clinical trial.Lancet Infect Dis. 2024; (published online March 6. https://doi.org/10.1016/S1473-3099(24)00077-X.)PubMed Google Scholar have reported the interim results of a phase 3 study that was conducted to evaluate the safety and immunogenicity of a bivalent subunit vaccine (NVX-CoV2373 + NVX-CoV2540), which contained the spike protein of the ancestral strain and Omicron BA.5 as a heterologous booster in adults previously vaccinated with COVID-19 mRNA vaccine.6Bennett C Woo W Bloch M et al.Immunogenicity and safety of a bivalent (omicron BA.5 plus ancestral) SARS-CoV-2 recombinant spike protein vaccine as a heterologous booster dose: interim analysis of a phase 3, non-inferiority, randomised, clinical trial.Lancet Infect Dis. 2024; (published online March 6. https://doi.org/10.1016/S1473-3099(24)00077-X.)PubMed Google Scholar To determine the immunogenicity of the bivalent subunit COVID-19 vaccine, Bennett and colleagues6Bennett C Woo W Bloch M et al.Immunogenicity and safety of a bivalent (omicron BA.5 plus ancestral) SARS-CoV-2 recombinant spike protein vaccine as a heterologous booster dose: interim analysis of a phase 3, non-inferiority, randomised, clinical trial.Lancet Infect Dis. 2024; (published online March 6. https://doi.org/10.1016/S1473-3099(24)00077-X.)PubMed Google Scholar tested IgG and neutralising antibody levels against the ancestral strain, Omicron BA.5, and XBB.1.5. The bivalent vaccine induced better neutralising activity against Omicron BA.5 and XBB.1.5 when compared with the prototype subunit vaccine (NVX-CoV2373) at day 28 after a two-dose booster. The authors found that the geometric mean titre (GMT) of anti-Omicron BA.5 neutralising antibodies at day 28 after the second dose of the bivalent vaccine was 1017·8 (95% CI 891·0–1162·6), and there was a 3·6-fold (95% CI 3·2–4·2) increase of GMT in comparison from the level at day 0. In the prototype vaccine group, the GMT of neutralising antibodies against Omicron BA.5 at day 28 was 515·1 (450·4–589·0) with 1·8-fold increase than that at day 0. In a monovalent BA.5 vaccinated group, the GMT before adjustment was 1507·3 (1259·0 to 1804·5) at day 28, corresponding with the highest fold change seen in the study of 4.4 from day 0. The participants recruited in this phase 3 study previously received at least three doses of monovalent or bivalent mRNA vaccines. The authors concluded that the heterologous boosting strategy with the bivalent subunit vaccine can significantly enhance the pre-existing neutralising activity triggered by a previous mRNA vaccine.6Bennett C Woo W Bloch M et al.Immunogenicity and safety of a bivalent (omicron BA.5 plus ancestral) SARS-CoV-2 recombinant spike protein vaccine as a heterologous booster dose: interim analysis of a phase 3, non-inferiority, randomised, clinical trial.Lancet Infect Dis. 2024; (published online March 6. https://doi.org/10.1016/S1473-3099(24)00077-X.)PubMed Google Scholar As various COVID-19 vaccine platforms have been approved for emergency use, the heterologous prime-boost vaccination strategy has shown better immunogenicity than homologous vaccination strategies.4Wu JD Li JX Liu J et al.Safety, immunogenicity, and efficacy of the mRNA vaccine CS-2034 as a heterologous booster versus homologous booster with BBIBP-CorV in adults aged ≥18 years: a randomised, double-blind, phase 2b trial.Lancet Infect Dis. 2023; 23: 1020-1030Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 7Leung NHL Cheng SMS Cohen CA et al.Comparative antibody and cell-mediated immune responses, reactogenicity, and efficacy of homologous and heterologous boosting with CoronaVac and BNT162b2 (Cobovax): an open-label, randomised trial.Lancet Microbe. 2023; 4: e670-e682Summary Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 8Costa Clemens SA Weckx L Clemens R et al.Heterologous versus homologous COVID-19 booster vaccination in previous recipients of two doses of CoronaVac COVID-19 vaccine in Brazil (RHH-001): a phase 4, non-inferiority, single blind, randomised study.Lancet. 2022; 399: 521-529Summary Full Text Full Text PDF PubMed Scopus (279) Google Scholar, 9Khong KW Liu D Leung KY et al.Antibody response of combination of BNT162b2 and CoronaVac platforms of COVID-19 vaccines against Omicron variant.Vaccines. 2022; 10: 160Crossref PubMed Scopus (32) Google Scholar In a phase 2 trial conducted by Wu and colleagues,4Wu JD Li JX Liu J et al.Safety, immunogenicity, and efficacy of the mRNA vaccine CS-2034 as a heterologous booster versus homologous booster with BBIBP-CorV in adults aged ≥18 years: a randomised, double-blind, phase 2b trial.Lancet Infect Dis. 2023; 23: 1020-1030Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar an mRNA vaccine boosted the anti-Omicron BA.5 neutralising activity 45·7-fold, whereas the homologous inactivated virus vaccine boosted neutralising antibodies by 2·9-fold. Furthermore, better immune responses are also found in CoronaVac and BNT162b2 vaccination than homologous CoronaVac vaccination, and in ChAdOx1-S and BNT162b2 than homologous ChAdOx1-S.7Leung NHL Cheng SMS Cohen CA et al.Comparative antibody and cell-mediated immune responses, reactogenicity, and efficacy of homologous and heterologous boosting with CoronaVac and BNT162b2 (Cobovax): an open-label, randomised trial.Lancet Microbe. 2023; 4: e670-e682Summary Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 10Borobia AM Carcas AJ Pérez-Olmeda M et al.Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial.Lancet. 2021; 398: 121-130Summary Full Text Full Text PDF PubMed Scopus (286) Google Scholar Even though a homologous subunit vaccine strategy was not involved in the study, it was also found that the bivalent subunit vaccine as a heterologous booster significantly improved the humoral response in a population primed with the mRNA vaccine. For safety, Chijioke Bennett and colleagues6Bennett C Woo W Bloch M et al.Immunogenicity and safety of a bivalent (omicron BA.5 plus ancestral) SARS-CoV-2 recombinant spike protein vaccine as a heterologous booster dose: interim analysis of a phase 3, non-inferiority, randomised, clinical trial.Lancet Infect Dis. 2024; (published online March 6. https://doi.org/10.1016/S1473-3099(24)00077-X.)PubMed Google Scholar reported that the bivalent subunit vaccine was tolerated well, and that no participants withdrew from the study due to adverse events.6Bennett C Woo W Bloch M et al.Immunogenicity and safety of a bivalent (omicron BA.5 plus ancestral) SARS-CoV-2 recombinant spike protein vaccine as a heterologous booster dose: interim analysis of a phase 3, non-inferiority, randomised, clinical trial.Lancet Infect Dis. 2024; (published online March 6. https://doi.org/10.1016/S1473-3099(24)00077-X.)PubMed Google Scholar Although the cellular responses elicited by this vaccine were not studied, the robust neutralising antibody response against Omicron BA.5 and XBB.1·5 after two doses of the bivalent subunit vaccine showed that this vaccine can be used as an effective booster against Omicron variants. Heterologous boosting in COVID-19 mRNA vaccine participants was highly effective, and likely to be effective in those who were previously primed with an inactivated or an adenovirus vectored COVID-19 vaccines. This bivalent subunit vaccine will provide a useful option as a booster vaccine for older people and high-risk individuals, in particular, those who cannot or do not want mRNA variant vaccines. The final report of this bivalent subunit vaccine, which should include an analysis on the vaccine effectiveness and cellular responses, is eagerly awaited. Of note, recently, this subunit protein vaccine has been further updated to a monovalent XBB.1.5 version. IF-NH has received honoraria from Pfizer, Merck, and Gilead for lectures; has offered consultative advice on COVID-19 vaccines to Fosun, Sinovac, and Sinopharm; was on the Moderna data safety monitoring board for COVID-19 vaccine 2023; has offered consultative advice on anti-SARS-CoV-2 monoclonal antibody treatment to AstraZeneca; and received support for attending meetings from AstraZeneca and Merck. RZ declares no competing interests. Immunogenicity and safety of a bivalent (omicron BA.5 plus ancestral) SARS-CoV-2 recombinant spike protein vaccine as a heterologous booster dose: interim analysis of a phase 3, non-inferiority, randomised, clinical trialAll three coprimary endpoints were met in part 2 of the ongoing 2019nCoV-311 study. These data support the development of monovalent and/or bivalent vaccines for the most currently circulating variants, to optimise protection. With no new safety findings, further investigation of omicron-based subvariant vaccines is supported by the evidence. Full-Text PDF
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