Influence of SARS-CoV-2 breakthrough infection and age on humoral immunity post-three-dose COVID-19 vaccination

In a recent study posted to the medRxiv* preprint server, researchers briefly reported the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection and age on humoral immunity following a triple-dose SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccination.

Background

Two-dose coronavirus disease 2019 (COVID-19) mRNA vaccinations have been associated with waning natural antibody levels and lower responses against the highly immune-evasive SARS-CoV-2 Omicron variants. Therefore, to counteract this, third vaccine doses were given to immunocompromised and clinically vulnerable people to complete their preliminary vaccine regimens or as booster shots among the public globally. The triple-dose vaccinations improved protection against severe illness but did not stop pervasive Omicron-linked infections.

Few studies have evaluated the longevity of post-third-dose immune reactions throughout the adult age spectrum or contrasted vaccine-triggered to hybrid antibody reactions evoked by triple-dose vaccination followed by COVID-19 breakthrough infection. This information could guide the development and delivery of upcoming vaccine boosters.

The present work's authors previously found that after two doses of the SARS-CoV-2 vaccination, older adults had lower antibody reactions than younger adults but similar initial reactions following three doses.

About the study

In the current research, the scientists measured the SARS-CoV-2 Omicron- and wild-type (WT)-specific antibody levels and virus neutralization capability about six months after the third-dose vaccination across COVID-19-naive adults between the ages of 24 to 98.

The researchers examined 116 subjects, including a subgroup of 47 older adults and 69 healthcare workers (HCWs), who were SARS-CoV-2-naive until around one month after receiving the third vaccine dose. All subjects or the individuals authorized to make decisions for them submitted written informed consent before study enrolment. 

Based on the presence of serum antibodies against the SARS-CoV-2 nucleocapsid (N) protein, breakthrough COVID-19 incidence was detected using the Roche Diagnostics Elecsys anti-SARS-CoV-2 test in conjunction with diagnostic (rapid-antigen-test or polymerase chain reaction (PCR)-based) data. The team noted that during follow-up, one-third of subjects developed SARS-CoV-2 infection (likely caused by Omicron), allowing for further comparison of hybrid and vaccine-induced immune reactions.

Results and discussions

According to the study results, a third dose of the SARS-CoV-2 mRNA vaccine significantly improves COVID-19-naive patients' antibody responses, including those against the Omicron variant, especially in older adults. The magnitudes of Omicron- and WT-specific anti-receptor-binding domain (RBD) binding immunoglobulin G (IgG) levels were similar at one, three, and six months after the third dose in older and younger adults and decreased at comparable rates. Yet, Omicron-specific reactions were invariably approximately 0.6 log₁₀ lower versus WT.

In addition, the sustained WT-selective angiotensin-converting enzyme 2 (ACE2) displacement and neutralization capacities were comparable between groups. In contrast, relative to younger adults, older adults showed lower Omicron-selective neutralization at three and six months following the third dose and reduced Omicron-selective ACE2 displacement ability at six months after the third dose. Congruent with this, older adults had impaired Omicron-targeting antibody reactions demonstrated by decreased antibody concentrations. 

Notably, six months after the third dose, antibody reactions in COVID-19-naive subjects of all ages had significantly declined to or below levels initially evoked by the two-dose vaccination. During this time, 96% of older and 56% of younger adults had Omicron neutralization capacity below the limit of quantification.

On the contrary, after receiving three doses of vaccination, both older and younger adults who contracted their first SARS-CoV-2 infection (likely from Omicron BA.2 or BA.1 variants) showed better binding and functional humoral reactions than those brought on by triple vaccination only. Omicron spike (S) protein exposure was most likely responsible for the observation that immunological augmentation was most prominent for Omicron-specific responses and advanced to antibody function. In that case, the researchers suggested that heterologous booster vaccination using variant S antigens would provide comparable advantages.

Conclusions

Overall, the study findings demonstrated that among SARS-CoV-2-naive subjects, antibody levels post-triple-dose vaccination were similar across age groups over time. In older adults, Omicron-specific neutralization decreased more quickly. Further, post-vaccine COVID-19 breakthrough infections elevated Omicron- and WT-specific responses over three-dose vaccination alone, demonstrating the advantages of hybrid immunity.

The study data propose that SARS-CoV-2-naive patients, mainly older adults, might benefit from a second booster shot in six months, despite highlighting the immunological advantages of third or booster doses for all ages. Contrarily, those who developed their first SARS-CoV-2 infection after receiving three doses of the vaccine might benefit less from a booster shot during this time.

When compared to vaccination with current, WT-only COVID-19 vaccines, Omicron-like antigen exposures, whether via infection or a multivalent vaccine containing variant S or RBDs, will probably induce better immune reactions against presently circulating viral variants. The authors stated that more research is required to determine the longevity of hybrid immune responses and the degree of cross-reactivity against newly developing virus strains.

*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

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.