Immune responses in Omicron breakthrough COVID-19
The ongoing spread of coronavirus disease 2019 (COVID-19) has been driven by the emergence of new highly transmissible variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that are often also capable of escaping the antibodies elicited by either vaccination or infection with the earlier strains. The latest of these is the Omicron, with over 30 mutations in the receptor-binding domain of the spike protein of the virus.
A recent study examined the question as to whether vaccination protects against Omicron infection by assessing breakthrough infection rates in participants at a superspreader event. The researchers found evidence suggesting broadly neutralizing responses against variants of the virus following Omicron, in contrast to Delta.
A preprint version of the study is available on the medRxiv* server, while the article undergoes peer review.
Omicron shot into the spotlight with its multiple spike protein mutations, including over 15 in the receptor-binding domain alone, the part that engages with the host cell receptor, the angiotensin-converting enzyme 2 (ACE2). Some of these have already been characterized in other variants, having been shown to confer greater infectivity, transmissibility, and antibody escape.
More recent studies indicate a higher degree of spread and a 40-fold reduction in neutralizing efficacy of neutralizing antibodies elicited by the Pfizer vaccine when tested against Omicron. Bioinformatics data shows that most of the epitopes bound by immunodominant T cells are conserved, unlike antibody-binding epitopes.
The researchers in the current study looked at the immune responses to the occurrence of Omicron breakthrough infections.
What did the study show?
The results show that both Omicron and Delta breakthrough infections were mild, with none of the patients requiring hospitalization. This was attributed to the activation of pre-existing adaptive immunity induced by vaccination against the virus. Omicron-infected patients showed some signs of platelet activation, monocyte activation, and tissue damage.
In these patients, too, CD8+ T cells against the Omicron spike were activated, in almost every spike-specific clone, indicating that activation or memory markers were being expressed. Conversely, Delta-infected patients showed terminal differentiation of effector T cells. However, other virus-specific T cells showed no increase in frequency or difference in phenotype, ruling out the activation of unrelated clones in the so-called bystander effect.
Thus, the Delta breakthrough infection produced the expected vaccine boost response, in contrast to the T cell activation caused by the Omicron breakthrough. The latter is typically found in primary infection of the unvaccinated. In both types of infection, spike-specific CD8+ T cell frequency was markedly higher than in vaccinated but healthy controls, but the rise was lower with Omicron.
Omicron cases were more likely to have non-spike-targeting CD8+ T cells than Delta, with memory markers compared to the effector phenotype of the latter. In vitro T cell responses to the spike peptides were higher with Omicron, including the release of inflammatory and antiviral IL-2, IFN-γ, and TNF cytokines. Such responses were borderline in healthy vaccinated controls but strong at three to six months in convalescent patients.
Both strains produced T cells reactive to other viral peptides but with lower responses than in recovered convalescent patients, indicating the presence of a potent vaccine-spike-specific CD8+ T cell response coupled with newly forming immunity to multiple viral antigens with diverse epitopes. The Delta infection promoted cytotoxic CD8+ T cells, perhaps because of the terminal effector function.
T follicular helper (Tfh) cells were reduced in frequency in Omicron cases but were activated; however, type 1 T helper cells (Th1) showed reduced chemokine receptor expression. This could be because B cells and T cells collaborate in the antiviral response, along with Tfh cells being retained within the lymph nodes. Th cells induced by the vaccine were still functioning at higher levels in Omicron cases than healthy vaccinated controls.
Omicron cases did not show any increase in anti-spike or anti-RBD B cells, though Delta cases did. Still, immunoglobulin G (IgG) anti-RBD antibodies did show a marked increase, indicating a vaccine boost. This response was stronger in Delta cases, which were also more responsive to RBD stimulation than uninfected or Omicron patient serum.
The large increase in Spike-specific plasmablasts was most noticeable, about half being IgG-secreting, along with activated spike-specific IgG-producing memory B cells. This indicates an infection-related rise in differentiated plasmablasts and activated memory B cells elicited by the vaccine for both breakthrough infection variants.
What are the implications?
The current study produced evidence suggestive of protective T cell immunity in convalescents, more with Omicron than with Delta. In the latter scenario, effector differentiation was observed rather than activation. T cell responsiveness increased when faced with the viral spike, along with robust new T cell responses to other non-spike viral antigens. This suggests that the infection was producing a broadly neutralizing response.
Along with this, the IgG anti-RBD response showed a surge, along with a rise in IgG-producing plasmablasts or memory B cells specific to the spike and RBD.
With a 75% breakthrough Omicron infection rate, it is clear that antibody escape from Pfizer or Moderna vaccine-induced antibodies has occurred, coupled with the waning of neutralizing antibodies over the three to six months that intervened between vaccination and the superspreader event.
In a situation of immune escape, the immune response will depend on the relationship between the T cell response elicited by the vaccine and the B cell responses to the Omicron breakthrough infection. However, earlier studies show that the Omicron mutations do not impact immunodominant antigens on the spike protein. Moreover, this variant may activate the protective T cell immunity elicited by the vaccine, as confirmed by this study.
Thus, T cell memory is key to protective immunity, as hinted by the persistence of T cell responses to the earlier SARS-CoV, even after nearly two decades, observed by other researchers. T cell immunity also mediates rapid viral clearance and recovery from infection, protecting against severe disease even at low antibody levels and thus aborting the infection in healthy individuals.
The T cell activation seen in Omicron vs. Delta may be due to the antibody escape seen with the former, which could also mean that durable broad T cell protective immunity is likely. At the same time, the earlier vaccination produced functional Th cells and rapidly responding IgG-producing class-switched spike- and RBD-specific plasmablasts and memory B cells.
These B cells are capable of binding to Alpha, Beta, and Gamma variants of the virus. They can thus churn out functional and neutralizing antibodies to Omicron following germinal center responses in the lymph nodes.
It is likely but remains to be demonstrated that the B cell responses will provide adapted anti-Omicron [neutralizing antibodies] as a result of the germinal centre response and that concerted T and B cell immunity as seen here will provide broad and long-term protection against SARS-CoV-2.”
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.
Kared, H. et al. (2022) "Immunity in Omicron SARS-CoV-2 breakthrough COVID-19 in vaccinated adults". medRxiv. doi: 10.1101/2022.01.13.22269213. https://www.medrxiv.org/content/10.1101/2022.01.13.22269213v1
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