COVID-19 vaccine development

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

A collection of human samples is being analyzed to examine in detail humoral and cellular immunity after natural infection. These patients recovered from infection and accepted to donate convalescent plasma for transfer to hospitalized patients in an approved clinical trial. The immune response of these cohort is studied longitudinally to identify the nature and longevity of immune response. In addition, the recipient patients will be studied in an effort to identify benefits of immunotherapy after plasma transfer. The results of analysis of natural infection will be important in the design of vaccine strategies. The identification of patients with high titers of neutralizing antibodies will also support the selection of plasma collection for transfer to hospitalized patients as immunotherapy. We studied SARS-CoV-2 antibody maintenance in this cohort of infected convalescent people in Athens, Greece. SARS-CoV-2 antibody kinetics eight months from COVID-19 onset: Persistence of spike antibodies but loss of neutralizing antibodies in 24% of convalescent plasma donors was observed. We continue to follow this cohort for 14 months and we determine Antibody longevity and neutralizing activity. In collaboration with Dr. Felber's Section we have developed DNA vectors that induced strong immune response in macaques after two vaccinations. Our strategy is to induce both neutralizing Ab and also cellular immunity able to optimally suppress virus infection. Several forms of SARS-CoV-2 antigens were expressed in DNA vectors and were tested in animals after characterization. Macaque vaccination showed that the animals develop robust immune responses. We showed that these responses to be protective after virus challenge, thus giving the opportunity to develop prophylactic vaccines against SARS-CoV-2 based on DNA technology that also provides much higher cellular immune responses. These responses may lead to vaccines with superior longevity and effectiveness compared with the current generation. 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 coronavirus disease 2019 (COVID-19)-infected individuals (NCT04743388). Transient increases in interleukin-15 (IL-15) and interferon gamma (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 increases in IL-15, IFN-gamma, and IP-10/CXCL10 after the 1st vaccination, which were enriched by tumor necrosis factor alpha (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 expanded our studies to immunocompromised individuals including patients with hematological malignancies, a population at high risk of developing severe disease upon SARS-CoV-2 infection. Protection afforded by vaccination is frequently low and the biology leading to altered vaccine efficacy is not fully understood. Overall, the patients showed heterogeneous adaptive and innate responses with lower humoral (binding and neutralizing antibodies) and reduced innate cytokine responses (IFN-gamma, IL-15 and IP-10/CXCL10 signature) to vaccination compared to naive vaccine recipients. Changes in IFN-g and IP-10/CXCL10 at priming vaccination and IFN-g, IL-15, IL-7 and IL-10 upon booster vaccination correlated with the Spike antibody magnitude and were predictive of successful antibody development. The pattern of responses described offer novel prognostic approaches for potentiating the effectiveness of COVID-19 vaccination in transplant patients with hematological malignancies. We are expanding our research of the development of adaptive and innate immune responses upon COVID-19 vaccination to other cancer cohorts.