SARS-CoV-2 breakthrough infection leads to distinct neutralizing antibody response

Scientists have worked at an unprecedented speed to develop effective vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causal agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Although COVID-19 vaccination has reduced hospitalization and mortality rates, many breakthrough infections following SARS-CoV-2 vaccination have been reported.

Study: Vaccine Breakthrough Infection with the SARS-CoV-2 Delta or Omicron (BA.1) Variant Leads to Distinct Profiles of Neutralizing Antibody Responses. Image Credit: ustas7777777 /


Breakthrough infections have been mostly associated with specific SARS-CoV-2 variants, such as the Beta, Delta, and Omicron variants of concern (VOCs). There remains a lack of documents regarding the predisposing factors that are linked with breakthrough infection and the consequences of breakthrough infection for SARS-CoV-2 immunity.

However, breakthrough infections are believed to occur as a result of both host- and viral- factors. For instance, immunocompromised patients with poor immune systems are typically at a higher risk even after vaccination.

Previous studies have reported breakthrough infections, even after detecting neutralizing activity in patients’ serum at the time of infection. These studies have also indicated that although T-cell activity to SARS-CoV-2 peptides remains effective against many SARS-CoV-2 variants, the neutralizing activity to certain variants like Omicron decreases significantly.

Researchers have stated that the occurrence of breakthrough infection among vaccinated persons has become a common phenomenon due to the emergence of new SARS-CoV-2 variants. Therefore, it is important to understand the breadth and efficacy of COVID-19 vaccines against a specific variant, as this would provide a better insight into the effectiveness of currently available SARS-CoV-2 vaccines.

About the study

In a new study published on the medRxiv* preprint server, scientists hypothesize that antibody-specific responses vary during vaccine breakthrough infections in a variant-specific manner. Their study cohort included fifty ambulatory individuals with symptomatic breakthrough infection who were characterized on the basis of their viral genotype, viral load by quantifying total spike- and nucleocapsid-antibodies using enzyme-linked immunosorbent assay (ELISA), and host antibody responses during breakthrough infection and following recovery.

In this study, the researchers obtained nasal swab samples and blood samples at the time of acute SARS-CoV-2 infection, which was typically four days after the onset of symptoms. Additional nasal swab samples were obtained after recovery, which was an average of seventeen days after the onset of symptoms.

Study findings

Nasal swabs from breakthrough infections exhibited decreased anti-spike antibody titers. Furthermore, antibody binding and neutralizing antibody titers were inversely correlated with viral loads at the time of breakthrough infection.

Interestingly, neutralizing antibodies generated in response to BA.1 Omicron infection exhibited a greater breath against Delta, BA.1, and BA.2 pseudoviruses. Such antibody responses were not observed during the Delta variant infection.

Taken together, these findings correlate with those of a previous study, which had shown that among unvaccinated individuals, neutralization titers were inversely correlated with the SARS-CoV-2 viral load.

The researchers also found that unvaccinated patients had 38-fold lower neutralization titers against BA.2, 33-fold lower against D614G, and 25-fold lower against Delta as compared to boosted or vaccinated patients. Thus, when vaccinated patients are infected by Delta or Omicron variants, they appear to elicit high neutralizing antibody titers.

In comparison to the Delta variant, Omicron infection exhibited the broadest antibody responses. Furthermore, a subset of Delta-infected individuals demonstrated no neutralizing antibody activity against the Omicron variants.

A. The logarithm of viral load at the time of infection vs the concentration of anti-Spike antibodies at the time of breakthrough. A regression line with standard error is shown, with the Pearson correlation coefficient and corresponding p value. B. Genotype-matched neutralizing antibody titers. A regression line with standard error is shown, with the Pearson correlation coefficient and corresponding p value. C. Anti-Spike antibody concentration at the initial study visit for culture-positive cases (+) and culture negative cases (−). Significance according to an unpaired Wilcoxon rank-sum test is shown. * – p < 0.05. D. Kaplan-Meier curves for time to PCR conversion by tertile of anti-Spike responses. The P-value represents log-rank testing comparing the subgroups.


The findings from the current study are potentially relevant to SARS-CoV-2 epidemiology. The Omicron variant became the dominantly circulating variant in many countries across the world because of its high transmissibility, ability to evade antibodies induced by previous SARS-CoV-2 infection or vaccination, and its ability to cause vaccine breakthrough infections and reinfections.

Recently, researchers have recently revealed that the BA.2 Omicron variant might replace BA.1 and become the dominant variant in many areas. Among all tested variants, BA.2 showed the lowest neutralization titers.

BA.1-infected and vaccinated individuals exhibited a more expansive neutralizing antibody repertoire as compared to Delta-infected and vaccinated individuals. This finding suggests a strategy associated with the development of a COVID-19 booster vaccine that could remain effective against several other SARS-CoV-2 variants. In the future, more studies are needed to define the durability of immune responses against current and future SARS-CoV-2 variants.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Seaman, S. M., Siedner, M. J., Boucau, J., et al. (2022). Vaccine Breakthrough Infection with the SARS-CoV-2 Delta or Omicron (BA.1) Variant Leads to Distinct Profiles of Neutralizing Antibody Responses. medRxiv. doi:10.1101/2022.03.02.22271731.

Posted in: Medical Research News | Disease/Infection News

Tags: Antibodies, Antibody, Assay, Blood, Cell, Coronavirus, Coronavirus Disease COVID-19, covid-19, Efficacy, Enzyme, Epidemiology, immunity, Mortality, Omicron, Pandemic, Peptides, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, T-Cell, Vaccine

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Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.

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