In a recent study posted to the medRxiv* pre-print server, researchers investigated whether neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein offered adequate immunity against breakthrough infections (BTIs) among vaccinated individuals.

Study: Correlation between post-vaccination titres of combined IgG, IgA, and IgM anti-Spike antibodies and protection against breakthrough SARS-CoV-2 infection: a population-based longitudinal study (COVIDENCE UK). Image Credit: Studio Romantic/Shutterstock

Previously only clinical trial studies have attempted to identify a robust correlate of vaccine-induced protection against SARS-CoV-2, so their findings cannot be generalized to the general population. Moreover, determining vaccine efficacy and risk of post-vaccination SARS-CoV-2 BTIs as a correlate of neutralizing antibody titers is both resource and time-intensive.

A population-scale study providing insights into the mechanisms of post-vaccination protective immune responses would accelerate licensure for several coronavirus disease 2019 (COVID-19) vaccine candidates.

About the study

In the present study, researchers launched a population-based observational study of COVID-19 in the UK, termed COVIDENCE UK, on May 1, 2020. All the study participants were UK residents over 16 years of age.

The researchers followed up on all the study participants for over a month, asking them to fill out monthly questionnaires to capture extensive information related to vaccine status, incident SARS-CoV-2 infection, determinants of vaccine response, and SARS-CoV-2 exposure. These monthly questionnaires allowed a detailed evaluation of exposure risks, capturing time-varying behaviors, such as interactions with other households.

During the study, the researchers sent a kit containing instructions, lancets, and blood spot collection cards to all the participants vaccinated with two doses or a one-dose regimen of the ChAdOx1 or BNT162b2 vaccines.

Using a commercially available enzyme-linked immunosorbent assay (ELISA), the researchers analyzed dried blood spot eluates collected from all the study participants. The ELISA assay used for the study offered 98.3% specificity and 98.6% sensitivity and effectively captured combined antibody titers of immunoglobulin (Ig) G (IgG), IgA, and IgM.

A subset of subjects attended an in-person visit to donate blood samples that permitted the measurement of neutralizing antibody titers in serum for the determination of interferon-gamma (IFN-γ) concentrations. These whole blood samples were stimulated for 24 hours with lyophilized peptides covering the coding sequence of the SARS-CoV-2 S.

For statistical investigation of the incidences of breakthrough infections, the researchers used data from those participants who had not received a booster dose and for whom post-vaccination anti-S IgG/A/M titer was available. The follow-up began from the day of blood sample collection to 13 days after their booster vaccination; however, follow-up was truncated at 18-weeks to maximize both the number of participants and the number of breakthrough infections included in the analysis.

The researchers used receiver operating characteristic (ROC) curve analysis to assess the strength of anti-S IgG/A/M titers as a predictor of breakthrough infection in all participants and then stratified by vaccine type.

A minimally adjusted logistic regression model was employed to further adjust for variables reflecting the risk of SARS-CoV-2 exposure, such as household factors, travel outside of the UK, and the number of weekly visits to the shops, to other indoor public spaces, etc.

Using Stata's roccomp command, the researchers performed a final comparison of the area under the ROC curve between the minimally and fully adjusted models.

Findings

Based on the hypothesis that high anti-S IgG/A/M titers would correlate positively with reduced risk of BTIs in vaccinated individuals, the researchers determined the predictive strength of combined IgG, IgA, and IgM responses to the SARS-CoV-2 S protein. While they found a strong correlation between anti-S IgG/A/M and neutralizing antibody titers, they observed a weaker correlation between anti-S IgG/A/M titers and S peptide-stimulated whole blood IFN-γ responses.

Post-six to seven months after primary vaccination, anti-S IgG/A/M titers only moderately predicted breakthrough SARS-CoV-2 infections, although predictions improved substantially when key SARS-CoV-2 exposure variables were taken into account. These findings cast doubt on the effectiveness of anti-S IgG/A/M titers as a standalone correlate of protection for COVID-19 vaccines. 

Moreover, anti-S IgG/A/M titers failed to capture cellular immune responses, as demonstrated by the weak correlation observed between anti-S IgG/A/M titers and S peptide-stimulated IFN-γ concentrations.

Conclusion

Although humoral and cellular immune responses are sometimes correlated, they can sometimes be dissenting. The study findings validating the same showed that anti-S IgG/A/M titers alone were inadequate to predict the risk of BTIs after COVID-19 vaccination. The combined measure of anti-S IgG/A/M was only modestly predictive of BTIs in vaccinated individuals, thus, was unable to reflect protective COVID-19 vaccine-induced cellular responses.

*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.

Written by

Neha Mathur

Neha Mathur has a Master’s degree in Biotechnology and extensive experience in digital marketing. She is passionate about reading and music. When she is not working, Neha likes to cook and travel.