How does the interval between the 1st and 2nd BNT162b2 doses impact the neutralization breadth and potency against variants of concern?

In a recent study posted to the medRxiv* preprint server, scientists explored the influence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) extended gap vaccination on the variants of concern (VOCs) neutralization. They also analyzed the impact of Omicron breakthrough infections post-triple vaccination on the SARS-CoV-2 VOCs neutralization.

Study: The effect of Omicron breakthrough infection and extended BNT162b2 booster dosing on neutralization breadth against SARS-CoV-2 variants of concern. Image Credit: Irina Shatilova/Shutterstock
Study: The effect of Omicron breakthrough infection and extended BNT162b2 booster dosing on neutralization breadth against SARS-CoV-2 variants of concern. Image Credit: Irina Shatilova/Shutterstock

Background

The coronavirus disease 2019 (COVID-19) Pfizer/BioNTech BNT162b2 messenger ribonucleic acid (mRNA) vaccine received approval in the United Kingdom (UK) in December of 2020. In January 2021, a change in UK policy necessitated the administration of the BNT162b2 booster vaccine with an extended interval of eight-to-12 weeks instead of the two doses given at three-to four-week intervals specified by the initially approved strategy.

Two shots were initially necessary for most COVID-19 vaccines to be effective against the SARS-CoV-2 Wuhan strain, Delta, and Alpha VOCs. Nevertheless, the third vaccination with either mRNA-1273 or BNT162b2 became advised due to the decline in vaccine-triggered neutralizing antibody (nAb) concentrations and the appearance of the Omicron BA.1 VOC, which encodes over 30 mutations in the spike (S) glycoprotein.

Studies demonstrated that a third vaccine shot could boost neutralization titers and restore the vaccine's effectiveness against the Omicron BA.1 variant. Yet, in contrast to earlier dominant variants, breakthrough infections in vaccinated people were more frequent during Omicron BA.1 VOC dominance.

About the study

In the current work, the researchers compared the breadth and magnitude of the nAb reaction and the S-reactive memory B cell levels in two-and three-dose SARS-CoV-2 vaccinated individuals. They analyzed people who received a second COVID-19 BNT126b2 vaccine dose at a short interval (three-four weeks) or extended interval (eight to 12 weeks). Further, the study volunteers were immunized with a third vaccine shot approximately six to eight months later.

The team collected peripheral blood mononuclear cells (PBMCs) and plasma from 19 and 28 individuals receiving the BNT162b2 vaccine with a short booster interval designated as a short-group and an extended booster interval termed as an extended-group, respectively. Immunoglobulin G (IgG) adherence to recombinant SARS-CoV-2 Wuhan-1 S protein was determined using an enzyme-linked immunosorbent assay (ELISA). Subsequently, the investigators assessed the half-maximal binding (median effective dose, or ED50) to recombinant SARS-CoV-2 Wuhan-1 S protein.

Further, plasma neutralization potency and breadth were examined using human immunodeficiency virus 1 (HIV-1) lentiviral particles pseudotyped with the SARS-CoV-2 S of Wuhan-1 (vaccine strain), Omicron BA.1, Beta, Delta, or Alpha VOCs and a HeLa cell line as the target cell persistently expressing angiotensin-converting enzyme 2 (ACE2).

The scientists determined whether a longer gap between the second vaccine dose improved the size of the memory B cell reaction and the nAb reaction breadth. They evaluated the nAb response's persistence after two-dose vaccination and the effect of the third booster dose on the nAb response.

The investigators examined if broader neutralization was associated with higher avidity of S-targeting antibodies. Furthermore, they analyzed a third booster dose's effects on Omicron sublineage neutralizations. Besides, the researchers assessed the BA.2/BA.1 breakthrough infections impact on triple vaccinated participants during the UK Omicron surge between January and February 2022. 

Results

The study results demonstrated that a longer gap between the first and second doses of the BNT162b2 vaccination broadens SARS-CoV-2 neutralization breadth in four different ways. 

Initially, in line with earlier studies, after the second immunization, there was an elevation in IgG adherence (ED50) to S protein across the extended booster cohort. Secondly, the S-reactive IgG binds more avidly post-second dose vaccination following extended intervals. Thirdly, the eight to 12-week gap produced more extensive SARS-CoV-2 VOC neutralizing action, including the Omicron BA.1 VOC. Finally, SARS-CoV-2 naive people getting a second booster vaccine dose after an extended interval exhibited a higher proportion of S-reactive IgG+ memory B cells.

However, regardless of the time between the first and second vaccinations, a third dose produced a significant and widespread neutralizing reaction against SARS-CoV-2 VOCs, leading to generally comparable rates of cross-neutralizing activity in both the extended and short booster groups. Concurrently, the short booster group's S-reactive IgG adhesion avidity enhanced, indicating ongoing affinity maturation.

Interestingly, the neutralizing activity towards the antigenically distant Omicron BA.1, BA.2, and BA.4/BA.5 VOCs heightened among both groups following a third vaccination shot. Neutralization titers against the SARS-CoV-2 D614G strain, BA.2, BA.1, and BA.4/BA.5 variants further improved in the triple vaccinated group after breakthrough infection during the UK Omicron BA.2 or BA.1 surge, independent of prior COVID-19 history.

Conclusions

The study findings showed that an extended gap between the initial two COVID-19 vaccine doses could drastically broaden the immune response and produce a higher percentage of S-reactive memory B cells. A third dose vaccination, however, causes comparable immunological responses and S-reactive memory B cells between the extended and short groups.

Furthermore, the authors demonstrated that the third shot of the vaccine improves neutralizing activity against the SARS-CoV-2 Omicron BA.2, BA.1, and BA.4/BA.5 sublineages. The breakthrough SARS-CoV-2 infection during the UK Omicron BA.2 and BA.1 waves further augmented the neutralization capacity among triple-vaccinated subjects.

Overall, the study data were significant to vaccination plans in groups where SARS-CoV-2 vaccine coverage is still low. It also offers guidance on tailoring vaccination schedules to achieve the broadest possible neutralization breadth.

*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:
Shanet Susan Alex

Written by

Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.

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