Breakthrough Omicron BA.1/BA.2 infections in the triple-vaccinated linked to broad-based immunity

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The Omicron variant of concern (VOC) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread rapidly, displacing earlier variants worldwide. It caused large numbers of breakthrough infections even in those people who had hybrid immunity (“generated through a combination of vaccination and infection”). Serological studies indicated this was associated with suboptimal immune reactions in triple-vaccinated people.

Study: Omicron BA.1/BA.2 infections in triple-vaccinated individuals enhance a diverse repertoire of mucosal and blood immune responses. Image Credit: Fit Ztudio/Shutterstock
Study: Omicron BA.1/BA.2 infections in triple-vaccinated individuals enhance a diverse repertoire of mucosal and blood immune responses. Image Credit: Fit Ztudio/Shutterstock

A new study looked at the whole spectrum of immunological reactions raised by spike and non-spike antigens following Omicron BA.1/BA.2 infections in such individuals, both with and without prior SARS-CoV-2 infection.


The Omicron variant rapidly mutated into several sublineages, from BA.1/BA.2 to BA.4/5. The currently circulating variants include BA.2.75, BQ.1, and XXB. Omicron is remarkable for the very large number of spike mutations that led to its evasion of vaccine- and infection-induced immunity.

At present, three doses of a messenger ribonucleic acid (mRNA) vaccine are recommended for protection against adverse outcomes following SARS-CoV-2 infection. However, the risk of symptomatic coronavirus disease 2019 (COVID-19) has been reduced by 67% at 2-4 weeks from the third dose but less than 50% at ten weeks or later. This means that up to 85% of people in some regions have hybrid immunity.

Earlier hybrid immunity was elicited chiefly by Alpha or earlier variants of the virus, also called ancestral variants. These individuals reacted with stronger antibody and T-cell responses to the vaccine doses than uninfected people. With Omicron, though, some scientists claim that the immune response to this VOC is strikingly muted following a breakthrough infection, especially if the patients already had a prior ancestral infection that led to immune imprinting.

To explore this hypothesis, the current paper, posted online to the preprint server medRxiv*, examined circulating and mucosal immunity in triple-vaccinated healthcare workers (HCW) before and after they were infected with BA.1 or BA.2. The HCW were first classified into those with and without a prior history of ancestral SARS-CoV-2 infection (“infected” and “infection-naïve” individuals, respectively).

What did the study show?

About 40% of the cohort had SARS-CoV-2 infection prior to the first vaccine dose, with a median gap of ~540 days. All except one patient was infected before December 2020, thus probably with the ancestral variant. Breakthrough infections occurred between December 21, 2021, and May 17, 2022, two-thirds caused by BA.1 and the rest by BA.2.

Following triple-vaccination, the ancestral infection elicited higher NAb titers to ancestral and BA.1/BA.2 strains compared to the responses in infection-naïve people. Serum IgA against the spike was also higher, and anti-nucleocapsid (anti-N) immunoglobulin G (IgG), though the latter showed waning over time. Anti-spike and anti-N sIgA levels in nasal fluid were comparable, but T cell responses were higher after ancestral infection.

The findings of the study show that Omicron infection does produce lower neutralizing titers of Omicron-specific antibodies in those with a prior history of ancestral infection and who are triple-vaccinated, compared to the infection-naive. However, neutralizing antibody (NAb) levels do rise in most such people.

The infection-naïve showed a significant rise in NAbs to ancestral variants and to BA.1/BA.2 and BA.5, by two-fold and 6-8-fold, respectively. Those with prior ancestral infection showed no rise to the ancestral variants and 60-70% rise to Omicron subvariants.

Anti-N IgG increased in both groups after Omicron infection, but more in those with prior ancestral infection, all of whom attained detectable levels vs. 77% of the infection-naïve group.

T-cell responses to the spike were found to rise only in infection-naïve individuals following Omicron infection. Still, those with prior ancestral infection showed markedly higher T cell responses after Omicron infection.

These previously-infected individuals appear to have maximally induced responses with a CD8+ phenotype of high cytotoxic potential after their 3rd mRNA vaccine.”

Antibody and T cell responses also rose markedly to viral antigens other than the spike in all individuals but higher in those with prior ancestral infection. These T-cells were more mature and highly cytotoxic in the latter group. “Our findings suggest that an infection prime followed by 3 mRNA vaccine doses results in maximally induced spike-specific T cell responses, with limited potential for further boosting, at least in the short term.”

This might indicate that exposure order is important in T-cell response efficacy.

The nasal mucosal lining showed increased secretory immunoglobulin A (sIgA) after Omicron infection in all individuals, irrespective of prior infection, corresponding with non-spike-specific antibodies and T cells. The nasal lining fluid was able to inhibit the binding of the ancestral spike to the angiotensin-converting enzyme 2 (ACE2) molecule much better in the infection-naïve group compared to the other, but both showed increased inhibition of BA.2/BA.5 spike-ACE2 binding.

What are the implications?

An ancestral infection could dampen Omicron-induced anti-spike responses in triple-vaccinated individuals for unknown reasons. Immunologic imprinting, or greater immunity to Omicron leading to lower viral loads and poor antigen exposure, are two suggested explanations. Some research also indicates the possibility of impaired B cell receptor signaling after the third dose of vaccine in previously infected individuals.

 However, omicron infection in triple-vaccinated individuals generally enhances immune responses to SARS-CoV-2 in both blood and mucosa and is likely to contribute to ongoing population immunity against COVID-19.” This is supported by real-world data, say the scientists.

Mucosal immunity is important in protecting against infection and preventing transmission but is not remarkable with the current vaccines. Omicron breakthrough infections might help induce this form of protective immunity.

The hybrid immunity induced by Omicron breakthrough infections is complex and occurs in different compartments. Serologic findings alone do not provide a picture of the immune boost that occurs following Omicron infections, which could help protect against future Omicron variants.

We have demonstrated that immune components not induced by currently available vaccines such as mucosal and non-spike responses are enhanced by viral infection. These may play a critical role in accumulating protective immunity to SARS-CoV-2, but should also be prioritised as targets to broaden the responses generated by the next generation of vaccines.”

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