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Principal Investigator: BARBARA K FELBER
Organization: DIVISION OF BASIC SCIENCES - NCI
Fiscal Year: 2021
Award: $650,195
Funding agency: National Cancer Institute
To characterize immune responses in SARS-CoV2 infected persons we examined a cohort of infected persons over 10 months post symptoms onset. Elucidating the characteristics of human immune response against SARS-CoV-2 is of high priority and relevant for determining vaccine strategies. We reported the results of a follow-up evaluation of anti-SARS-CoV-2 antibodies in 148 convalescent plasma donors who participated in a phase 2 study at a median of 8.3 months (range 6.8-10.5 months) post first symptom onset. Monitoring responses over time, we found contraction of antibody responses for all four antigens tested, with Spike antibodies showing higher persistence than Nucleocapsid antibodies. A piecewise linear random-effects multivariate regression analysis showed a bi-phasic antibody decay with a more pronounced decrease during the first 6 months post symptoms onset by analysis of two intervals. Interestingly, antibodies to Spike showed better longevity whereas their neutralization ability contracted faster. As a result, neutralizing antibodies were detected in only 76% of patients at the last time point. In a multivariate analysis, older age and hospitalization were independently associated with higher Spike, Spike-RBD, Nucleocapsid, N-RBD antibodies and neutralizing antibody levels. Results on persistence and neutralizing ability of anti-SARS-CoV-2 antibodies, especially against Spike and Spike-RBD, should be considered in the design of future vaccination strategies. We also reported on a cohort of patients very early upon symptom onset which were part of clinical protocol of convalescent plasma (CP) infusion. CP might also develop into a safe and effective treatment modality based on re-cent studies and meta-analyses; however, little is known regarding the kinetics of antibodies in CP recipients. To evaluate the kinetics, we followed 31 CP recipients longitudinally enrolled at a median of 3 days post symptom onset for changes in binding and neutralizing antibody titers and viral loads. Antibodies against the complete trimeric Spike protein and the receptor binding domain (Spike-RBD), as well as against the complete Nucleocapsid protein and the RNA binding domain (N-RBD) were determined at baseline and weekly following CP infusion. Neutralizing antibody titers were determined at the same timepoints. Viral loads were determined semi-quantitatively by SARS-CoV-2 PCR. Patients with low humoral responses at entry showed a robust increase of antibodies to all SARS-CoV-2 proteins and NAb reaching peak levels within 2 weeks. The rapid increase in binding and neutralizing antibodies was paralleled with a concomitant clearance of the virus within the same timeframe. Patients with high humoral responses at entry demonstrated low or no further increases; however, virus clearance followed the same trajectory as in patients with low antibody response at baseline. Together, the sequential immunological and virological analysis of this well-defined cohort of patients early upon infection shows increased presence of high levels of binding and neutralizing antibodies and potent clearance of the virus. To characterize adaptive and innate immune responses in SARS-CoV2 vaccinated persons we reported a study describing early responses to vaccination that are important in shaping both humoral and cellular protective immunity. Dissecting innate vaccine signatures may predict immunogenicity to help optimizing efficacy of mRNA and other vaccine strategies. We characterized the cytokine and chemokine responses to the 1st and 2nd dose of the BNT162b2 mRNA (Pfizer/BioNtech) vaccine in antigen-naive and in previously COVID-19-infected individuals (NCT04743388). Transient increases in IL-15 and IFN-gamma levels early after boost correlated with Spike antibody levels, supporting their use as biomarkers of effective humoral immunity development in response to vaccination. We identified a systemic signature including IL-15, IFN-gamma and IP-10/CXCL10 increase after the 1st vaccination, which was enriched by TNF-alpha and IL-6 after the 2nd vaccination. In previously COVID-19-infected individuals, a single vaccination resulted in both strong cytokine induction and antibody titers similar to the ones observed upon booster vaccination in antigen-naive individuals, a result with potential implication for future public health recommendations. We are now expanding this study to analyze responses in vaccinated cancer patients and to different SARS-CoV2 vaccine platforms. The urgent need for a vaccine to combat the COVID-19 pandemic prompted us to apply our decades of experience in developing HIV vaccines towards SARS-CoV-2. We have long practical experience in the development and application of nucleic acid vaccine regimens. We use this vaccine platform due its versatility, simplicity, scalability, and lack of eliciting immunity against the vector. The use of a nucleic acid-based vaccine provides a simple method allowing efficient expression and post-translational modifications of structurally complex immunogens and results in the development of both humoral and cellular immunity. Immune responses can be maintained for long periods and can be boosted by the same or heterologous boosting strategies. Over many years we have successfully optimized different steps to obtain improve immunogenicity including optimized vaccine regimens, vaccine delivery, immunogen selection, adjuvant selection, and combination vaccine regimens. The speed of development, versatility and efficacy of mRNA-based vaccines have been amply demonstrated in the case of SARS-CoV-2. DNA vaccines represent an important alternative since they induce both humoral and cellular immune responses in animal models and in human trials. Anti-Spike neutralizing antibodies provide strong protection against SARS-CoV-2 infection in animal models, and correlate with protection in humans, supporting the notion that induction of strong humoral immunity is key to protection. The DNA-only vaccine regimens were compared to a regimen that included co-immunization of Spike DNA and protein in the same anatomical site, the latter of which showed significant higher antibody responses. We found induction of robust antibody and T cell responses by different Spike DNA-based vaccine regimens able to effectively mediate protection and to control SARS-CoV-2 infection in the rhesus macaque model. All vaccine regimens led to control of SARS-CoV-2 intranasal/intratracheal challenge and absence of virus dissemination to the lower respiratory tract. Vaccine-induced binding and neutralizing antibody titers and antibody-dependent cellular phagocytosis inversely correlated with transient virus levels in the nasal mucosa. Importantly, a vaccine regimen comprising simultaneous co-immunization of DNA and Protein at the same anatomical site showed best neutralizing abilities and was more effective than DNA alone in inducing protective immune responses and controlling SARS-CoV-2 infection. Thus, an expansion of the DNA vaccine regimen to include co-immunization with Spike protein may be of advantage also for SARS-CoV-2.
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