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In an analysis involving more than 10 million North Carolina residents, Covid-19 vaccines were highly effective in preventing hospitalization and death up to 9 months after vaccination. Waning protection against infection over time was due to both declining immunity and the emergence of the delta variant.

Breakthrough infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in fully vaccinated individuals are receiving intense scrutiny because of their importance in determining how long restrictions to control virus transmission will need to remain in place in highly vaccinated populations as well as in determining the need for additional vaccine doses or changes to the vaccine formulations and/or dosing intervals. Measurement of breakthrough infections is challenging outside of randomized, placebo-controlled, double-blind field trials. However, laboratory and observational studies are necessary to understand the impact of waning immunity, viral variants and other determinants of changing vaccine effectiveness against various levels of coronavirus disease 2019 (COVID-19) severity. Here, we describe the approaches being used to measure vaccine effectiveness and provide a synthesis of the burgeoning literature on the determinants of vaccine effectiveness and breakthrough rates. We argue that, rather than trying to tease apart the contributions of factors such as age, viral variants and time since vaccination, the rates of breakthrough infection are best seen as a consequence of the level of immunity at any moment in an individual, the variant to which that individual is exposed and the severity of disease being considered. We also address key open questions concerning the transition to endemicity, the potential need for altered vaccine formulations to track viral variants, the need to identify immune correlates of protection, and the public health challenges of using various tools to counter breakthrough infections, including boosters in an era of global vaccine shortages.Here, Lipsitch and colleagues assess the impact of breakthrough SARS-CoV-2 infections that occur in individuals who have been vaccinated against COVID-19. The authors explain how the rate of breakthrough infections can be measured, what the causes of these infections are and discuss other key questions that need to be considered in light of these infections.

In an observational study involving nearly 440,000 veterans, both the BNT162b2 vaccine and the mRNA-1273 vaccine were highly effective at preventing infection, hospitalization, and death from Covid-19. Infection risks were approximately 21% lower with mRNA-1273 than with BNT162b2. Follow-up included periods when either the alpha variant or the delta variant was dominant.

The randomized trial assessing the efficacy of a single injection of the Ad26.COV2.S showed 56.3% vaccine efficacy beginning 14 days after injection and 52.9% efficacy more than 28 days after injection against moderate to severe–critical Covid-19. Protection lasted at least 6 months without an added boost. Vaccination was associated with mild-to-moderate adverse effects.

In the United States, more than 30,000 cases of mpox (formerly known as monkeypox) had occurred as of March 1, 2023, in an outbreak disproportionately affecting transgender persons and gay, bisexual, and other men who have sex with men. In 2019, the JYNNEOS vaccine was approved for subcutaneous administration (0.5 ml per dose) to prevent mpox infection. On August 9, 2022, an emergency use authorization was issued for intradermal administration (0.1 ml per dose); however, real-world effectiveness data are limited for either route. We conducted a case-control study based on data from Cosmos, a nationwide Epic electronic health record (EHR) database, to assess the effectiveness of JYNNEOS vaccination in preventing medically attended mpox disease among adults. Case patients had an mpox diagnosis code or positive orthopoxvirus or mpox virus laboratory result, and control patients had an incident diagnosis of human immunodeficiency virus (HIV) infection or a new or refill order for preexposure prophylaxis against HIV infection between August 15, 2022, and November 19, 2022. Odds ratios and 95% confidence intervals were estimated from conditional logistic-regression models, adjusted for confounders; vaccine effectiveness was calculated as (1 - odds ratio for vaccination in case patients vs. controls) × 100. Among 2193 case patients and 8319 control patients, 25 case patients and 335 control patients received two doses (full vaccination), among whom the estimated adjusted vaccine effectiveness was 66.0% (95% confidence interval [CI], 47.4 to 78.1), and 146 case patients and 1000 control patients received one dose (partial vaccination), among whom the estimated adjusted vaccine effectiveness was 35.8% (95% CI, 22.1 to 47.1). In this study using nationwide EHR data, patients with mpox were less likely to have received one or two doses of JYNNEOS vaccine than control patients. The findings suggest that JYNNEOS vaccine was effective in preventing mpox disease, and a two-dose series appeared to provide better protection. (Funded by the Centers for Disease Control and Prevention and Epic Research.).

Data from Singapore on BNT162b2 vaccination in children 5 to 11 years of age showed that during a period of omicron-variant predominance, BNT162b2 reduced the risks of SARS-CoV-2 infection and Covid-19–related hospitalization.

The effectiveness of the BNT162b2 and ChAdOx1 vaccines against new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections requires continuous re-evaluation, given the increasingly dominant B.1.617.2 (Delta) variant. In this study, we investigated the effectiveness of these vaccines in a large, community-based survey of randomly selected households across the United Kingdom. We found that the effectiveness of BNT162b2 and ChAdOx1 against infections (new polymerase chain reaction (PCR)-positive cases) with symptoms or high viral burden is reduced with the B.1.617.2 variant (absolute difference of 10–13% for BNT162b2 and 16% for ChAdOx1) compared to the B.1.1.7 (Alpha) variant. The effectiveness of two doses remains at least as great as protection afforded by prior natural infection. The dynamics of immunity after second doses differed significantly between BNT162b2 and ChAdOx1, with greater initial effectiveness against new PCR-positive cases but faster declines in protection against high viral burden and symptomatic infection with BNT162b2. There was no evidence that effectiveness varied by dosing interval, but protection was higher in vaccinated individuals after a prior infection and in younger adults. With B.1.617.2, infections occurring after two vaccinations had similar peak viral burden as those in unvaccinated individuals. SARS-CoV-2 vaccination still reduces new infections, but effectiveness and attenuation of peak viral burden are reduced with B.1.617.2. A large, community-based study in the United Kingdom indicates that the effectiveness of BNT162b2 and ChAdOx1 vaccines against SARS-CoV-2 infections with symptoms or high viral burden is reduced with the Delta variant compared to the Alpha variant.

Among 843,208 participants in Israel who were 50 years of age or older and had received two doses of the BNT162b2 vaccine at least 5 months earlier, those who received a booster had 90% lower mortality due to Covid-19 than those who did not receive a booster. The study period was 54 days; adverse effects were not recorded.

A study involving more than 94,000 vaccinated and unvaccinated adolescents between the ages of 12 and 18 years in Israel showed increasing levels of protection against Covid-19 during the first month after receipt of two vaccine doses. The estimated vaccine efficacy at 7 to 21 days after receipt of two doses was 90% against infection and 93% against symptomatic disease.

Unvaccinated persons without previous Covid-19 had the highest risk of omicron infection; those who had been infected after emergence of the delta variant and had received three mRNA vaccine doses were the most protected.