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Approach to SARS-Cov-2 Vaccination news & views COVID-19 A ‘mix and match’ approach to SARS-CoV-2 vaccination Heterologous dosing with the adenovirus-based ChAdOx1 (AstraZeneca) vaccine followed by an mRNA vaccine induced stronger immune responses than did the homologous ChAdOx1 vaccine series, according to recent immunogenicity studies. Meagan E. Deming and Kirsten E. Lyke espite the development of multiple Humoral immunity: successful vaccines against the Anti-spike IgG, neutralizing Dcoronavirus SARS-CoV-2, the titers and spike-specific B cells continued emergence of variants of concern and the sporadic worldwide distribution of Homologous mRNA vaccines vaccines have limited and will continue to limit vaccine effectiveness. A new wrinkle in the global vaccine effort has been the occurrence of rare events such as thrombosis and thrombocytopenia syndrome associated with adenovirus-based vaccines. This triggered cessation of the distribution of Heterologous vector or mRNA vaccines AstraZeneca’s ChAdOx1 nCoV-19 (ChAd) vaccine in many countries, as well as a surge in vaccine hesitancy in risk-averse 1 populations . Cellular immunity: SARS-CoV-2 In this issue of Nature Medicine, studies Spike-specific CD4+ + (and variants) 2 3 and CD8 T cells by Barros-Martins et al. and Schmidt et al. Homologous vector vaccines capitalize on the ad hoc heterologous prime– boost vaccination that resulted from the Fig. 1 | A heterologous SARS-CoV-2 vaccine platform induces strong immunity. Heterologous dosing halting of vaccination with ChAd in several with an adenovirus-based vaccine (ChAd) followed by an mRNA vaccine (either BNT or mRNA-1273) European countries, which left partially results in more-robust humoral immunity (orange arrow) and cellular immunity (red arrow) than does vaccinated people the option of completing homologous vaccination with adenovirus-based vaccines. The heterologous vaccine strategy improves their vaccinations with an mRNA vaccine the induction of spike protein–specific CD8+ T cells3 and neutralization of variants2 beyond that achieved (BNT162b2 (BNT), from Pfizer–BioNTech); by either of the homologous vaccine-dosing strategies. or mRNA-1273, from Moderna). Barros-Martins et al. report that, compared with results obtained by homologous ChAd– ChAd dosing, the ChAd–BNT dosing than after homologous ChAd–ChAd superiority of this strategy over homologous strategy resulted in significantly greater vaccination3. In addition, the participants prime–boost regimens for cellular responses immunoglobulin G (IgG) and IgA immune dosed with ChAd–mRNA demonstrate and neutralization of variants (Fig. 1). responses directed against the SARS-CoV-2 a greater number of circulating spike As indicated by these new studies, spike protein and robust, 20- to >60-fold protein–specific CD4+ and CD8+ T cells, validating the immunogenicity and greater titers of neutralizing antibody as well as cytokine-producing T cells, than reactogenicity of ‘mix and match’ dosing against the Alpha (B.1.1.7), Beta (B.1.351) that of participants dosed with ChAd– with different approved vaccines may offer and Gamma (P.1) SARS-CoV-2 variants ChAd. Schmidt et al. further demonstrate a solution that could help mitigate supply of concern2. These neutralizing titers were comparable multifunctional, spike protein– shortages and interruptions. The improved approximately threefold higher than those specific CD4+ T cell responses but greater immunogenicity outcomes also suggest in serum from the groups dosed with BNT– CD8+ T cell responses in the ChAd–mRNA that a heterologous vaccine approach may BNT (albeit with differing intervals between group3. A third study, published recently in overcome limitations of the individual dose 1 and dose 2), with higher titers of the Lancet, provides additional evidence that vaccine platforms. Immunogenicity in IgG and IgA subclasses. Similarly, Schmidt the heterologous ChAd–mRNA vaccine response to adenovirus-vectored vaccines et al. show significantly higher titers of IgG approach is well tolerated and stimulates is limited by pre-existing neutralizing antibodies directed against the SARS-CoV-2 a robust IgG and neutralizing-antibody antibodies to common adenovirus serotypes spike protein and receptor-binding domain response4. Combined, these studies show to which humans are exposed, and may after ChAd–mRNA (either BNT162b2 or improved immunogenicity outcomes with compromise the ability to mount an immune mRNA-1273) or mRNA–mRNA vaccination heterologous dosing and suggest possible response to the SARS-CoV-2 spike protein, 1510 NATURE MEDICINE | VOL 27 | SEPTEMBER 2021 | 1510–1517 | www.nature.com/naturemedicine news & views as was noted with the CanSino Biologics– investigate the ‘mix and match’ strategy in strategies have demonstrated advantageous Beijing Institute of Biotechnology’s a prospective manner. These heterologous immunogenicity outcomes, as measured adenovirus type 5–vectored formulation5. vaccine strategies may add further resilience by both humoral responses and cellular Using a non-human adenoviral vector, to SARS-CoV-2 vaccinations against the responses to the original SARS-CoV-2 and such as Astra Zeneca’s ChAd vaccine2, or backdrop of continually emerging variants. its variants. These innovative vaccine-dosing using heterologous recombinant adenovirus The probability that booster vaccines schedules may be required both as proof serotypes (rAd26 followed by rAd5), as may be required, either to stimulate against vaccine supply interruptions and seen for the Russian Gamaleya Sputnik V waning immunity or to expand the for maximizing immune responses, which vaccine6, enables adenovirus-based vaccine breadth of immunity to SARS-CoV-2 in turn will help to reduce the transmission platforms to deliver the SARS-CoV-2 spike protein lineage variants, further of emerging variants and protect spike protein in a way that will generate an highlights the importance of optimizing immunocompromised people. ❐ enhanced immune response. Nevertheless, the immunogenicity of vaccines. Thus adenovirus-based vaccine platforms are far, mRNA vaccines have demonstrated Meagan E. Deming and Kirsten E. Lyke ✉ limited in that they induce strong T cell continued efficacy against the B.1.1.7 Te Center for Vaccine Development and Global responses but are less effective at developing variant, with reduced but ongoing efficacy Health, University of Maryland School of Medicine, neutralizing antibody responses. against the B.1.351 and P.1 circulating Baltimore, MD, USA. Extensive pre-clinical and early-phase variants12. This suggests that the robust ✉e-mail: [email protected] clinical studies, particularly in the neutralizing antibody response induced development of vaccines against human by the mRNA platform may provide the Published online: 26 July 2021 immunodeficiency virus, have long amplitude of humoral immune response https://doi.org/10.1038/s41591-021-01463-x demonstrated the potential immunological needed to overcome the genetic mutations advantages of heterologous prime–boost within the SARS-CoV-2 variants. This References vaccination strategies. Neutralizing spike contrasts with the performance of the 1. Wise, J. Br. Med. J. 372, n699 (2021). 2. Barros-Martins, J. et al. Nat. Med. https://doi.org/10.1038/s41591- protein–specific antibodies are capable of AstraZeneca vaccine, which, despite 021-01449-9 (2021). preventing infection with SARS-CoV-2 in generating a robust T cell response, has 3. Schmidt, T. et al. Nat. Med. https://doi.org/10.1038/s41591-021- animal models, and these antibodies have been shown to perform poorly against the 01464-w (2021). served as the marker for a protective vaccine B.1.351 variant13. Given the ongoing threat 4. Borobia, A. M. et al. Lancet 398, 121–130 (2021). 5. Zhu, F. et al. Lancet 396, 479–488 (2020). response, although precise thresholds have of current and future circulating variants, 6. Logunov, D. Y. et al. Lancet 396, 887–897 (2020). not been confirmed in humans7. Although studies exploring alternative sequence 7. Corbett, K. S. et al. Preprint at bioRxiv https://doi. seroconversion is more readily assessed, booster strategies (e.g., viral vector after org/10.1101/2021.04.20.440647 (2021). 8. Tarke, A. et al. Cell Rep. Med. https://doi.org/10.1016/j. T cell responses also contribute to viral nucleic acid platform), additional vaccine xcrm.2021.100355 (2021). clearance after infection; these may generate doses after a complete SARS-CoV-2 vaccine 9. Cucchiari, D. et al. Am. J. Transplant. https://doi.org/10.1111/ a more-robust response to recently emergent series (wild-type boost), or variant booster ajt.16701 (2021). 10. Kardani, K., Bolhassani, A. & Shahbazi, S. Vaccine 34, 413–423 variants, and may be generated even in the doses after wild-type primary vaccination (2016). absence of detectable antibody responses are ongoing or in development. Additionally, 11. Spencer, A. J. et al. Nat. Commun. 12, 2893 (2021). in immunocompromised transplant the interval between prime and boost 12. Liu, Y. et al. N. Engl. J. Med. 384, 1466–1468 (2021). 8,9 13. Madhi, S. A. et al. N. Engl. J. Med. 384, 1885–1898 (2021). recipients . Incorporating vaccines that probably has a critical role. 14. Takkar, A. et al. Cancer Cell https://doi.org/10.1016/j. elicit mainly humoral responses (e.g., These strategies may be of particular ccell.2021.06.002 (2021). protein-based vaccines) and those that elicit importance in enhancing immune strong cellular responses (e.g., viral vector– responses in immunocompromised Acknowledgements based vaccines) into heterologous
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