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Principal Investigator: Lothar Hennighausen
Organization: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Fiscal Year: 2022
Award: $2,134,432
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Objective 1
SARS-CoV-2 infection ranges from asymptomatic to severe with lingering symptomatology in some. We have conducted three clinical studies addressing newly emerging questions and problems as the pandemic progressed. Although a large percentage of infected individuals are asymptomatic, the response of their immune systems and prevalence of unrecognized ongoing inflammation to SARS-CoV-2 was not understood at the time the pandemic started in the spring of 2020. Originally, we addressed this question and investigated immune transcriptoms in individuals from one of the original super spreading events in Europe (PMID: 33608566).
As the pandemic progressed, variants of concern (VOC) carrying specific mutations thought to enhance viral fitness have emerged. We investigated the immune response of hospitalized patients infected with the Alpha (PMID: 35181735), Beta (PMID: 35465056) and Omicron (PMID: 35784346) variants and the benefits of prior vaccination with the mRNA vaccine BNT162b. The Beta variant was of particular concern because it carries the mutation E484K within the receptor binding domain (RBD), which has been demonstrated to enhance escape from neutralizing antibody inhibition in vitro and may be linked with reduced vaccination efficacy. In February 2021 it was reported that the Alpha variant had also acquired the E484K spike mutation.
The Alpha+E484K variant is fast spreading, prompting interest in the response of both unvaccinated and vaccinated individuals to disease from this variant. Recent in vitro data demonstrated that this mutation led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies, suggesting that this variant represents a threat to the efficacy of the BNT162b2 vaccine. However, it had remained unclear whether these variants elicit a modified immune response in patients. To fill this knowledge gap, we investigated differences in the immune transcriptome in hospitalized patients infected with either the native Alpha variant or the Alpha+E484K variant. RNA-seq conducted on PBMCs isolated within five days after the onset of COVID symptoms demonstrated elevated activation of specific immune pathways, including JAK-STAT signaling, in Alpha+E484K patients. Longitudinal transcriptome studies demonstrated a delayed dampening of interferon-activated pathways in Alpha+E484K patients. Prior vaccination with BNT162b vaccine reduced the transcriptome inflammatory response to Alpha+E484K infection relative to unvaccinated patients. Acquisition of the single amino acid change E484K in the Alpha background elicits an altered immune response, which could impact disease progression.
The Beta variant carrying the escape mutation E484K in the receptor binding domain was of particular concern due to reduced immunological protection following vaccination. We investigated the immune transcriptome of elderly individuals (average age 82 yr.) from an old peoples home, who were infected with the Beta variant (PMID: 35465056). Immune transcriptomes established from PBMCs after the onset of COVID-19 symptomology revealed a more intensive immune response in BNT162b vaccinated patients as compared to unvaccinated ones. Transcription factors linked to the JAK/STAT pathway, interferon stimulated genes, and genes associated with innate antiviral immunity and COVID-19 were highly enriched in vaccinated patients.
Omicron, the most recent variant, is highly infectious and antibody response following infection is reported to be less robust than that to other variants. Our most recent study investigated how prior vaccination and/or prior infection modulates that response (PMID: 35784346). Disease severity, antibody responses and immune transcriptomes were characterized in four groups of Omicron-infected outpatients (n=83): unvaccinated/no prior infection, vaccinated/no prior infection, unvaccinated/prior infection and vaccinated/prior infection. The percentage of patients with asymptomatic or mild disease was highest in the vaccinated/no prior infection group (87%) and lowest in the unvaccinated/no prior infection group (47%). Significant anti-Omicron spike antibody levels and neutralizing activity were detected in the vaccinated group immediately after infection but were not present in the unvaccinated/no prior infection group. Within two weeks, antibody levels against Omicron, increased. Omicron neutralizing activity in the vaccinated group exceeded that of the prior infection group. No increase in neutralizing activity in the unvaccinated/no prior infection group was seen. The unvaccinated/prior infection group showed an intermediate response. We then investigated the early transcriptomic response following Omicron infection in these outpatient populations and compared it to that found in unvaccinated hospitalized patients with Alpha infection. Omicron infected patients showed a gradient of transcriptional response dependent upon whether they were previously vaccinated or infected. Vaccinated patients showed a significantly blunted interferon response as compared to both unvaccinated Omicron infected outpatients and unvaccinated Alpha infected hospitalized patients typified by the response of specific gene classes such as OAS and IFIT that control anti-viral responses and IFI27, a predictor of disease outcome.
Significance and impact: Anti-Omicron spike antibody levels and neutralizing activity were higher in the vaccinated group immediately after infection but were not present in the unvaccinated group without prior infection group.
Our human-subject and clinical data contribute to ongoing large-scale efforts by many labs to understand the spectrum of immune response elicited by SARS-CoV-2 infection, the contribution of variants and effects of prior vaccination.
Objective 2
In December 2020, the U.S. Food and Drug Administration issued the first emergency use authorization (EUA) for a vaccine for the prevention of COVID-19 caused by SARS-CoV-2). Although highly effective against the original SARS-CoV-2 strain, efficacy against variants of concerns can be substantially lower. As 100s of millions of citizens world-wide receive mRNA-based as well as vector-based vaccines, the innate immune responses are unclear and are only beginning to be investigated. There is an urgent need to understand the immune response mounted in different population groups. Among those are the response of young versus old and the response of individuals that had been previously infected. Equally, and maybe even more critical, is an understanding of the immune response in immunocompromised individuals, such as cancer patients as well as those with organ transplants.
We have conducted three studies to address some of these questions with partners in Austria and South Korea. Knowledge about the impact of prior SARS-CoV-2 infection of the elderly on mRNA vaccination response is needed to appropriately address the demand for additional vaccinations in this vulnerable population. We showed that octogenarians, a high-risk population, mount a sustained SARS-CoV-2 spike-specific immunoglobulin G (IgG) antibody response for 15 months following infection (PMID: 35395191). This response boosts antibody levels 35-fold upon receiving a single dose of BNT162b2 mRNA vaccine 15 months after recovery from coronavirus disease 2019 (COVID-19). In contrast, antibody responses in naive individuals boost only 6-fold after a second vaccine. Spike-specific angiotensin-converting enzyme 2 (ACE2) antibody binding responses in the previously infected octogenarians following two vaccine doses exceed those found in a naive cohort after two doses. RNA sequencing (RNA-seq) demonstrates activation of interferon-induced genetic programs, which persist only in the previously infected. A preferential increase of specific immunoglobulin G heavy chain variable
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