Immunocompromised in the Omicron Era

How does prior vaccination and infection impact immunity to the highly transmissible Omicron variant in immunocompromised transplant recipients?
Immunocompromised in the Omicron Era

As many as 3% of the population in Canada and the US are estimated to be immunocompromised, meaning one or more components of their immune system are comparatively weak or absent. One of the largest groups of immunocompromised people is solid organ transplant recipients (SOTR), who receive grafts including kidneys, lungs, hearts, and livers to remedy end-stage organ disease. SOTR often receive lifelong immunosuppression to prevent transplanted tissues from being attacked by the recipient’s immune system, which respond to anything that is foreign to the body. As a result, SOTR are at higher risk for severe infections and vaccine failure compared to the immune-competent general public.

Anxieties about COVID-19 still loom over many immunocompromised people. Studies by our group and others revealed that SOTR not only experienced increased severity of COVID-19 disease but were found to generate poorer SARS-CoV-2 vaccine responses 1-4. These findings pushed regulatory agencies including the FDA to recommend three vaccine doses to complete the primary immunization series, and fourth- and fifth-dose as boosters. Concerns have also been raised about the potential for resistance–associated viral mutations appearing in immunocompromised hosts, due in part to protracted infection with SARS-CoV-2 5. The vulnerability of these patients to severe COVID-19 and the related public health implications underscore the need to understand the immune response to SARS-CoV-2 in these patients. 

This is particularly true in light of the highly contagious Omicron variant, which was first characterized late in 2021 6. Following its emergence, rates of infection rose significantly as existing immunity (through vaccination or natural infection) provided little protection against symptomatic infection. The Omicron BA.1 subvariant resulted in high numbers of hospitalizations and deaths in Canada, despite high community vaccination rates, and an apparent reduced virulence compared to earlier strains of SARS-CoV-2. One reason was Omicron’s significant variability in the spike protein, leading to immune evasion against neutralizing antibodies (humoral immunity) 7. On the other hand, T-cell responses (cellular immunity) were generally well conserved between Omicron and ancestral SARS-CoV-2 8. The impact of Omicron on immunocompromised patients, who experience dysfunction in both humoral and cellular immunity, is poorly understood, leaving may many patients in a place of uncertainty, unsure of how protected they are even after three or more doses of vaccine. Further, among those who recover from COVID-19, it is unknown how such prior experiences provide cross-protective responses against newer circulating subvariants.

In our study we evaluated binding antibodies, neutralizing antibodies, and T-cell responses in transplant recipients across a variety of clinical scenarios with a focus on the Omicron BA.1 and BA.2 subvariants, as these were the dominant circulating types during the study period. We recruited four groups of patients (Fig 1): Cohort 1 consisted of SOTR who developed COVID-19 before Omicron subvariants started circulating, including strains corresponding to the original SARS-CoV-2, and variants of concern like Alpha and Delta. Most of these patients were unvaccinated at the time of infection because they were enrolled in the pre-vaccination era. Cohort 2 consisted of SOTR who had recently recovered from infection with Omicron BA.1. Most patients in this group were vaccinated with the majority receiving three or four doses of vaccine prior to their infection. Cohort 3 consisted of SOTR who had received three doses of the mRNA-1273 (Moderna) vaccine and had no documented history of COVID-19. Lastly, Cohort 4 consisted of health care workers receiving three doses of the Pfizer-BioNTech vaccine (BNT162b2), included for comparison.  

Figure 1 - Overview of study cohorts

Among SOTR, we observed the most robust Omicron BA.1-directed neutralizing antibody and T-cell responses in the group recovered from recent BA.1 infection, with immune responses comparable to triple-vaccinated health care worker controls. Further, in this group a strong cross-reactive neutralizing response was observed against Omicron BA.2, ancestral SARS-CoV-2, and Delta variant. On the other hand, three vaccine doses in SOTR without history of infection do generate neutralizing and T-cell responses against BA.1, but the former was substantially lower compared to those with hybrid immunity (infection plus vaccination). Similarly, SOTR with prior non-Omicron infection were found to mount poor neutralizing antibody responses to BA.1, despite having strong responses to ancestral SARS-CoV-2 and Delta variant. Together these results suggest that highly immunized SOTR recently recovered from BA.1 infection induce a breadth of neutralizing responses against SARS-CoV-2 including antibodies that can neutralize other highly transmission subvariants, including Omicron BA.2. Although prior vaccination may have contributed to the robust immune responses observed in this group, the number of vaccine doses received prior to infection was not associated with the magnitude of antibody or T-cell response, suggesting that recent BA.1 infection may be the primary driver of the immune response in this situation.

We were surprised by the degree to which infection with BA.1 increased the magnitude of the neutralizing antibody and T-cell response in (mostly) vaccinated SOTR. In the pre-Omicron era, we showed that antibody and T-cell responses in SOTR were higher after infection than vaccination with two-doses of mRNA vaccine 3,9. Here we find further evidence of immune discrepancies between immune-competent and immunocompromised groups. In transplant patients, natural infection, specifically with the circulating variant, may be needed for robust immune responses, while in immune-competent people 3-dose vaccination has been found to induce neutralization comparable to the infection 10,11. Although our data show a quantifiable difference in immune response, deliberate exposure to SARS-CoV-2 is discouraged because of the high risk for serious COVID-19 complications. Our results underscore the need for additional preventive measures to protect vulnerable immunocompromised hosts, including alternative vaccination formulations, prophylactic monoclonal antibodies, and antivirals like Paxlovid.  

It's hard to predict what these results will mean for immunocompromised patients moving forward. Due to comparatively lower neutralizing antibody and T-cell responses, transplant recipients with prior (pre-Omicron) infection or vaccination alone may be at risk for symptomatic infection with Omicron subvariants. However, recent data suggests that despite these lower responses, prior receipt of ≥3 mRNA vaccine doses was associated with significantly reduced disease severity from natural Omicron infection in SOTR 12. In the current study, vaccinated SOTR recovered from Omicron BA.1 infection developed potent neutralizing response at magnitudes similar to triple-vaccinated immune-competent controls, including cross-neutralizing responses to BA.2. Consequently, the risk for reinfection and severe disease may be comparatively mitigated in this group.   



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