Delta breakthrough infections elicit potent, broad and durable neutralizing antibody responses

Abstract

The SARS-CoV-2 Delta variant is currently responsible for most infections worldwide, including among vaccinated individuals. Although these latter infections lead to milder COVID-19 disease relative to unvaccinated subjects, the specificity and durability of antibody responses elicited by Delta breakthrough cases remain unknown. Here, we demonstrate that breakthrough infections induce serum binding and neutralizing antibody responses that are markedly more potent, durable and resilient to spike mutations observed in variants than those observed in subjects who were infected only or received only two doses of vaccine. We show that Delta breakthrough cases, subjects who were vaccinated after infection and individuals vaccinated three times (without infection) have serum neutralizing activity of comparable magnitude and breadth, indicating that multiple types of exposure or increased number of exposures to SARS-CoV-2 antigen(s) enhance antibody responses. Neutralization of SARS-CoV, however, was moderate, underscoring the importance of developing vaccines eliciting broad sarbecovirus immunity for pandemic preparedness.

Omicron BA.1 and BA.2 neutralizing activity elicited by a comprehensive panel of human vaccines

“…Here we report that, although the two Omicron sublineages evaluated are characterized by severe dampening of plasma neutralizing activity, vaccine and infection-elicited crossneutralization of BA.2 was more efficient than that of BA.1, independent of the immunization scheme or vaccine platform. Although mRNA vaccines induced the greatest magnitude of Omicron plasma neutralizing activity across all tested COVID-19 vaccines, administration of a booster dose increased neutralizing antibody titers and breadth against BA.1 and BA.2 to appreciable levels regardless of the vaccine evaluated, concurring with recent findings for BA.1 (5,13,16,(46)(47)(48). These results are consistent with previous studies demonstrating that a third vaccine dose results in the recall and expansion of pre-existing SARS-CoV-2 S-specific memory B cells, as well as de novo induction of novel ones, leading to production of neutralizing antibodies with enhanced potency and breadth against variants (49,50).…”

“…The emergence of the SARS-CoV-2 Delta and subsequently Omicron variants of concern led to an increasing number of reinfections and vaccine breakthrough cases (5,41,42). Public health policies were therefore updated worldwide to recommend administration of an additional vaccine dose (booster) several months after the primary vaccine series, which has been shown to increase the breadth and potency of neutralizing antibodies (5,13). We thus assessed and compared the benefits provided by homologous or heterologous vaccine boosters on vaccinee plasma neutralizing activity against G614, BA.1, and BA.2 S VSV pseudotypes.…”

“…The ongoing COVID-19 pandemic has led to the emergence of SARS-CoV-2 variants with increased transmissibility, viral fitness and immune evasion (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). The most recently named variant of concern, Omicron, is characterized by the greatest known genetic divergence from the ancestral virus (Wuhan-Hu-1) and consists of three sublineages designated BA.1, BA.2, and BA.3.…”

Potency and Breadth of Neutralization after 3 doses of mRNA vaccines in COVID-19 Convalescent and Naïve individuals

“…These results support the fact that repeated events of immune stimulation either by natural infection and/or vaccination are required to achieved maximum levels of neutralizing response with a wide breadth against SARS-CoV-2. The number of stimulation events is likely limited to three, since a third dose of an mRNA vaccine did not significantly increase the neutralizing levels achieved after two doses in COVID-19 convalescent patients, as it has been recently observed (8). In the naïve group the third dose of mRNA vaccine induced a clear boosting of neutralizing response in terms of potency and breadth that reached that was comparable for the first time to the levels of convalescents vaccinated.…”

Differences in transcriptional response underlie why prior vaccination exceeds prior infection in eliciting robust immune responses in Omicron infected outpatients

“…The highly transmissible Omicron (B.1.1.529) variant is less susceptible to neutralizing antibodies elicited by previous vaccination or other variant infection (1)(2)(3)(4), thus resulting in a continuation of the COVID-19 pandemic. While recent studies have investigated the antibody response to breakthrough infections (5,6), there is a knowledge gap about the humoral and genomic immune response to Omicron infection in outpatients that had been vaccinated, previously infected with another SARS-CoV-2 variant or both. Specifically, the impact of previous infection as compared to vaccination in the generation of anti-Omicron spike antibodies upon Omicron infection has yet to be determined.…”