Because of the rapid spread of SARS-CoV-2, deploying effective vaccination strategies requires not only the elicitation of protective immunity but also ensuring maximum coverage of this protective immunity in naive populations. As a result of SARS-CoV-2 vaccine shortages early in the COVID-19 pandemic, coupled with a need to deploy the first vaccine dose in naive populations, the intervals between prime and boost were not always uniform in different countries and/or regions. This provides a unique opportunity to evaluate if varying the time interval between the prime and boost leads to differential immune responses in naive people versus SARS-CoV-2-convalescent people. Although the current dose interval of most SARS-CoV-2 vaccines in clinical use range from 3 weeks to 4 weeks between prime and boost, extending this interval to 6–14 weeks can lead to higher levels of neutralizing antibodies and higher levels of CD4+ T cells that secrete the cytokine IL-2 in naive people from the UK1. In the current issue of Nature Immunology, Hall et al. assess an extended (8- to 16-week) BNT162b2 dose interval versus a standard (3- to 6-week) dose interval in healthcare workers from Canada2. Relative to antibody responses after the standard interval, the delayed interval offered superior neutralizing antibody responses to SARS-CoV-2, including the Alpha, Beta and highly transmissible Delta variants (Fig. 1). However, CD4+ and CD8+ T cell responses to SARS-CoV-2 showed dampened trends, although most of the differences were not statistically significant, after the delayed interval, relative to such responses after the standard vaccine interval. The differences in antibody and T cell responses in the delayed versus the standard dosing interval may, however, merely reflect the differences in B cell and T cell response kinetics to BNT162b2 vaccination3. Another interesting observation is that the delayed interval did not lead to higher frequencies of adverse events than did the standard interval. The implications of the T cell responses after the extended interval dose in the context of long-term protection are also unknown. A key question from this study that remains is whether the adaptive immune responses elicited by the delayed dose interval will translate into increased real-world vaccine efficacy against SARS-CoV-2 variants such as Omicron or even more diverse future variants. Moreover, as this study evaluated differences in neutralizing antibody responses and T cell responses in mainly female populations, it will be critical to also evaluate if similar immune responses are observed in an extended prime and boost interval in male populations.

Fig. 1: Neutralizing antibody responses in standard versus delayed vaccine dose interval in health care workers.
figure 1

A delayed 8- to 16-week vaccine dose interval between prime and boost leads to higher levels of neutralizing antibodies in vaccinated people than does a standard 3- to 6-week vaccine dose interval, in healthcare workers who are predominantly female.

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The development of SARS-CoV-2 vaccines, including clinical safety and efficacy testing to rapid rollout, is one of the greatest scientific, medical and public-health achievements in recent history. Several SARS-CoV-2 vaccines are safe and effective, and the mRNA–lipid nanoparticle (LNP) vaccines are arguably the most effective at protecting against severe COVID-19 and death4,5. Despite the high efficacy of the SARS-CoV-2 mRNA vaccines in preventing severe disease, the emergence of SARS-CoV-2 variants of concern can dampen vaccine efficacy6. In addition, the durability of immune responses that can protect against severe COVID-19 is uncertain.

As a result of the vaccine supply shortage during the early rollout of the SARS-CoV-2 vaccines, there was vigorous debate on the benefits versus risks of extending the interval between the first vaccine dose and second vaccine dose7. The rationale for the benefits included vaccinating as many people as possible with a single vaccine dose to provide partial immunity and potentially avoid severe COVID-19. This idea gained early traction because the vaccine efficacy was upward of 80–90% after a single dose and before the second dose, and even if the interval between the two doses was extended7. Thus, it was theorized that a single dose should at least reduce the incidence of severe disease in the vaccinated population. The opposing argument posited that the low levels of neutralizing antibodies from a single dose of mRNA–LNP vaccine could theoretically drive the emergence of variants that were partially or fully resistant to vaccine-elicited antibodies. However, a point that was less frequently discussed was the potential impact that delaying the second dose might have on vaccine-elicited immune responses. Notably, Hall et al. demonstrated a potential silver lining of delaying the second vaccine dose: the generation of higher levels of binding and neutralizing antibodies2. Tenfold higher levels of binding antibody responses to the receptor-binding domain of the SARS-CoV-2 spike protein were observed after the delayed dose interval. In addition, higher levels of neutralizing antibody levels against the ancestral SARS-CoV-2 and the Alpha, Beta and highly transmissible Delta variants were observed. As neutralizing antibody levels elicited by mRNA–LNP vaccines are probably a correlate of protection against COVID-198,9, strategies aimed at increasing neutralizing antibodies are of critical importance.

Although the finding of higher levels of immunity associated with protection from severe disease is certainly welcome news, it is important to also consider the nuances of this approach, especially in the setting of highly divergent variants such as Omicron or more genetically diverse variants that could emerge in the future. The ambiguity about the T cell responses elicited after delayed dosing, due to both limited sampling and the type of assay used, needs to be clarified with more-detailed studies, including granularity in the different T cell subsets. This issue is important, as it raises questions about protection from severe disease once neutralizing antibodies have waned to levels below those needed to block infection. In fact, studies have demonstrated that in the context of lower levels of neutralizing antibody responses, CD8+ T cells are critical for more rapid control of SARS-CoV-2 in animal models10. Although delaying the second dose results in clearly higher levels of neutralizing antibodies, the possibility of lowered T cell responses in this regimen should also be considered. Other key questions remain. What is the durability of these higher neutralizing antibody responses after the delayed dose? Does delaying the second dose also lead to a slower decrease in the levels of neutralizing antibody responses? Will these higher levels of neutralizing antibodies more rapidly curb the upper-respiratory airway transmission of divergent variants such as Omicron? It will also be important to evaluate the immunological basis for the improved humoral responses with delayed second dose and whether this effect would also apply to other mRNA vaccine strategies11,12,13 and protein-based constructs14. As previous studies have determined that germinal-center responses persist for several (7–15) weeks after vaccination in humans15, it will also be important to determine if delaying vaccine doses potentially leads to longer-lasting germinal-center responses and, as a result, more-mature and more-potent neutralizing antibodies at the monoclonal antibody level. This knowledge could have important implications for future pandemic vaccines. Ultimately, the fine tuning of vaccines for optimal immunity against SARS-CoV-2 and its variants will probably form part of the solution to one day end the COVID-19 pandemic.