Our data show evidence of diminished protection against symptomatic infection after receiving two doses of ChAdOx1-S or the BNT162b2 vaccine from 10 weeks after receiving the second dose. However, hospitalization and death protection were maintained at high levels for at least 20 weeks after receiving the second dose. 20 weeks or more after receiving the second dose, we observed more decreases with the ChAdOx1-S vaccine than with the BNT162b2 vaccine, although the groups receiving each vaccine were different.6 Declining protection against hospitalization was greater in older adults and in participants in a clinical risk group. However, among persons 65 years of age or older who were not in a clinical risk group, hospitalization protection remained close to 95% with the BNT162b2 vaccine and almost 80% with the ChAdOx1-S vaccine 20 weeks or more after receiving the second dose.
Our finding of declining vaccine efficacy against symptomatic disease is consistent with recent results from Israel and Qatar, which showed an increasing proportion of breakthrough cases among individuals who had received vaccines at the earliest.9,17-19 In addition to the emergence of the more transmissible delta variant, diminishing protection against symptomatic infection with increasing time since vaccination is likely to also contribute to the increase in the incidence of Covid-19 in the UK and elsewhere. However, the incidence of Covid-19-related hospitalizations and deaths has remained low, especially among vaccinated adults.20 Our finding of only limited declining protection against hospitalization or death in most of the groups we examined is consistent with the preserved vaccine efficacy against hospitalization observed in Qatar.9
Regional U.S. studies have also shown persistently high vaccine efficacy against Covid-19-related hospitalization despite the emergence and rapid local spread of the delta variant. Across 18 U.S. states, vaccine efficacy after receiving two doses of vaccine administered at 3-week intervals among adults (median age 59 years) who had been admitted to 21 hospitals between March 11 and July 14, 2021, was 86% (95%). CI, 82 to 88) total; vaccine efficacy was 87% (95% CI, 83 to 90) among patients with disease onset in the period from March to May compared with 84% (95% CI, 79 to 89) among patients with disease onset in the period from June to July 2021, without signs on a significant decrease in vaccine efficacy over a 24-week period.21 A similar study involving adults in New York in the period from May 3 to July 25, 2021, showed that hospitalization rates were almost 10 lower among vaccinated adults (> 90% of them had received two doses of mRNA vaccine for 3 weeks from each other) than among unvaccinated adults (1.31 vs. 10.69 per 100,000 person-days). Vaccine efficacy against hospitalization remained relatively stable (91.9 to 95.3%) during the monitoring period, although age-adjusted vaccine efficacy against new cases of Covid-19 decreased from 91.7% to 79.8%, a change that coincided with a increase in the circulation of the delta variant from less than 2% to more than 80% of cases.22 Conversely, an increased proportion of hospitalizations among infected adults who had been vaccinated at the earliest and had received two doses of the BNT162b2 vaccine at 3-week intervals in Israel have been reported.17 The shorter interval of 3 weeks as well as the longer follow-up in a population with rapid vaccine intake in Israel may be factors to explain this difference compared to results in the UK, USA and Qatar.
Our findings and the results from Qatar and the United States raise important questions about the timing of the third dose of vaccine in adults, which remains protected against hospitalization and death for at least 5 months after receiving two doses. Israel was one of the first countries to immunize adults with the BNT162b2 vaccine and began offering a third dose of the same vaccine to older adults from July 2021.23 Early data indicate that the third dose was associated with large reductions in the incidence of SARS-CoV-2 infection within 1 week after vaccination, with major reductions in the second week.23 However, the duration of protection offered by the third dose is uncertain. Many countries, including the United Kingdom and the United States, now offer a third dose.
A third dose vaccine enhances both humoral and cellular immunity to SARS-CoV-2 with increased neutralizing activity against various variants, including the delta variant, which is likely to improve protection against infection.24 The decrease in vaccine efficacy against severe disease outcomes was relatively limited in most cohorts in this study, but is likely to continue over time after receiving two vaccine doses. Decisions about the timing of the third dose should balance the rate of diminishing immunity to the occurrence of disease, including the risk of new variants, and the prioritization of individuals at greatest risk for serious disease. Existing evidence suggests that the efficacy of the vaccine increases with longer interval between doses, and if this also applies to third doses, the interval of administration should also be considered.25 At the same time, it is possible that third doses will be more reactogenic than previous doses, especially if the recipient receives different vaccines for the starting and booster doses.26 Attractive alternatives include half-dose boosters or boosters with variant-targeted vaccines, both of which are under investigation.27
For the UK and countries with administration intervals longer than the licensed interval, another important consideration is that the extended interval of 8 to 12 weeks between vaccine doses provides higher serological responses and increased vaccine efficacy than the licensed interval of 3 to 4 weeks for mRNA. vaccines,25 which can provide the peoples of these countries with better long-term protection.12 This hypothesis is supported by our current results, which compare short and long administration intervals among people aged 80 years or older.
We found that declining efficacy against hospitalization was greatest among individuals in clinical risk groups. Other studies have shown lower immune response and vaccine efficacy among individuals at clinical risk groups, especially those with immunosuppression.10,21,28,29 The UK and other countries are already recommending a third dose of Covid-19 vaccine to all adults as part of their primary immunization course.30.31
This study has some limitations. The test-negative case-control study design is observational and therefore subject to potential bias. The very narrow 95% confidence intervals in some analyzes relate to the large sample size and do not take into account what may be relatively larger effects of bias. A detailed quantification of potential bias is beyond the scope of this article, but others have assessed some biases such as exposure and outcome error classification using the test-negative design for inpatients and control participants.32 A full discussion of these limitations can be found in Section S3. The likely direction of these biases, if they exist, would be to reduce the effectiveness of the vaccine, where the reduction is greater at longer intervals after vaccination. Other limitations include our limited ability to assess decreasing vaccine efficacy against the alpha variant due to low circulation since June 2021. These estimates of vaccine efficacy also relate to the population of individuals seeking testing and were matched with the NIMS database, so they may not be representative of the entire population. For example, a higher proportion of non-white people than whites do not match the NIMS database. We also relied on test subjects declaring their symptoms when the test was requested, and some asymptomatic individuals may declare symptoms to access the test. Overall vaccine efficacy will be impaired if it is lower against asymptomatic infection and may mean for control participants that they were not matched based on exposure to an infectious disease that led to symptoms.
Our study showed evidence of significantly decreasing vaccine efficacy against symptomatic disease, but with limited decreasing against severe disease, for at least 5 months after an extended interval, two-dose schedule with the ChAdOx1-S and BNT162b2 vaccines. Decreasing vaccine efficacy was greater among older adults and among adults in clinical risk groups.