COVID-19 vaccines in the age of the delta variant.

The clinical development and global rollout of highly effective vaccines against SARS-CoV-2 has been unprecedentedly rapid. Nevertheless, viral evolution has continued at pace to the extent that questions are being raised about the continued effectiveness of first-generation vaccines in the face of variants of concern (VOCs). In particular, the rise of the delta variant (B.1.617.2) to become the dominant virus in most of the world has spurred efforts to assess vaccine effectiveness against VOCs and to understand the associated immune mechanisms of protection.

In The Lancet Infectious Diseases, Ramachandran Thiruvengadam and colleagues report on the effectiveness of the Oxford–AstraZeneca ChAdOx1 nCoV-19 vaccine in a test-negative, case-control study done in India during the delta variant outbreak of April, 2021. The effectiveness of complete vaccination (two doses) against RT-PCR-confirmed SARS-CoV-2 infection was 63·1% (95% CI 51·5–72·1); vaccine effectiveness against moderate-to-severe COVID-19 was higher than that for mild-to-moderate COVID-19 at 81·5% (95% CI 9·9–99·0), although the smaller sample size of severe cases affects the confidence we can have in this estimate. These data are consistent with studies of ChAdOx1 nCoV-19 vaccine effectiveness against the delta variant in the UK, which estimated an effectiveness of 60–67% against PCR-confirmed infection.3, 4

In 2020, early signals of high vaccine efficacy against both symptomatic and asymptomatic SARS-CoV-2 infection initially suggested that COVID-19 vaccines could be used to efficiently suppress viral transmission. However, with the emergence and rapid global spread of the delta variant, it now seems likely that vaccination will not provide complete protection against acquisition and onward transmission of SARS-CoV-2, which will continue to circulate for the foreseeable future.5, 6 Consequently, the goal of population-level vaccination has shifted to protecting both adults and children from developing severe disease, thereby preventing the excess mortality and stress on health-care systems that were observed in the early phases of the pandemic. The observation that ChAdOx1 nCoV-19 remains more than 80% effective at preventing moderate-to-severe COVID-19 following breakthrough infection with the delta variant reinforces the ongoing utility and importance of this widely distributed vaccine.

Importantly, Thiruvengadam and colleagues pair these epidemiological analyses with immunological data. In a group of ChAdOx1 nCoV-19 vaccine recipients, the authors assessed neutralising antibody titres and CD4 and CD8 T-cell responses against both wild-type (ancestral) and delta viruses, in an effort to understand the immunological responses that might moderate disease severity in the event of breakthrough infection. Neutralising antibody titres, which are strong predictors of vaccine efficacy, were markedly lower in ChAdOx1 nCoV-19 vaccine recipients when measured against the delta variant virus than when measured against wild-type SARS-CoV-2. Loss of neutralisation potency against the delta variant is not unique to the ChAdOx1 nCoV-19 vaccine; indeed, similar reductions have been reported using serum derived from cohorts vaccinated with mRNA vaccines.8, 9 By contrast with antibody responses, the high frequency of spike-specific CD4 and CD8 T cells elicited by ChAdOx1 nCoV-19 vaccination maintained recognition of both wild-type and delta variant spike peptides. In a comprehensive analysis, Thiruvengadam and colleagues showed that both T-cell cytokine secretion and activation were comparable following stimulation with either wild-type or delta spike peptide pools.

Considering the reduced antibody neutralisation but preserved T-cell recognition of the delta variant, these data raise the intriguing question of whether even low levels of neutralising antibodies are sufficient to prevent severe disease, or whether cellular immunity is a key factor in mitigating the risk of hospital admission. Ultimately, such questions will be difficult to answer in the absence of prospective cohort studies or early immune profiling of breakthrough infections. Such data would, however, crucially inform strategies for booster vaccination and the design of next-generation vaccine candidates.

We declare no competing interests.