In this program, our attempts are focused on understanding the contribution of Tfh cells and related subsets in driving the B cell output and antibody response in dengue. Dengue is an interesting model to understand the T-cell determinants of humoral immunity development. We are exploring the biology of Tfh-cell and related T-cell subsets in various outcomes of the dengue virus infection. Our current report from the patient cohort provides an insight into the cellular basis of antibody responses to dengue virus. We provide the first evidence of a peripheral T helper subset that showed the phenotypic resemblance to Tfh cells, and also the traits of help to B cells. We have developed a highly efficient antigen- specific T-B co-culture assay for measuring the T-dependent B cell responses, which work with as low as ~90 Ag-specific T cells (Cell Report Methods, 2022). We found that the novel Th-subset can provide help to B cells, has the potential of driving plasmablasts differentiation and induce the IgG production, as efficiently as the bonafide Tfh subset. We further observed that the novel Th-subset can induce productive cross-talk with both the naïve and memory B cells. We are now progressing to understand the transcriptomics landscape and the clonotype diversity of this newly identified CD4 + T cell subset at the single cell level, using 10X genomics platform. We also intend to develop a transgenic mouse model to further explore the origin of this novel subset.

Understanding the T-cell immunity to SARS-CoV-2 infection and vaccination is important to develop effective pan-coronavirus vaccines. We reported within a few months of the pandemic that the Indian population seems to have high  magnitude of the cross-reactive T cells that existed before COVID pandemic and may be generated due to exposure to common cold viruses.  The high level of cross-reactive CD4+ T cells prior to SARS-CoV-2 infection perhaps explains the less severe disease and lower rates of hospitalization in India (Frontiers Immunology, 2021). We are now conducting detailed investigations on the T cells in individuals who recovered from COVID-19 (Asymptomatic and mild) and received vaccination.

We recently provided the first evidence of the immunological effectiveness of the inactivated whole-virion COVID-19 vaccine COVAXIN®. We found that the vaccine induces robust immune memory to SARS-CoV-2 that was comparable with that following SARS-CoV- 2 infection in the levels of antibodies, memory B cells and memory T cells, up to 6 months post-vaccination. and variants of concern that persist for at least 6 months after vaccination. Although the SARS-CoV-2 variants may substantially impact the vaccine-induced antibodies, the T-cell response were highly preserved. Interestingly, the vaccine is not capable of inducing CD8 T cells and they are substantially impacted by the variants. We also found that the vaccine generated Tfh cells that are endowed with B cell help potential, similar to the Tfh cells induced after natural infection. This study provides important knowledge for evidenced-based policymaking on the future application of COVAXIN ® (Nature Microbiology, 2022). We are now extending these studies to understand the biology of Tfh cells in cases of sustained immunological memory.

While the laboratory’s research has focused on the exciting questions summarized above, we have made contributions outside of the core research efforts of the lab. We have established a “Human Immune Monitoring and T-cell Immunoassay” platform, with applications for the advanced immunological human trials of vaccines and biotherapeutics. The platform includes a variety of assays for measuring antigen-specific T cells and B cells in human blood – quantitation of virus-specific T cells, T-cell phenotype, T-cell functions, quantitation of polyfunctional T cells, measurement of anti-viral T cells, T-cell ability in developing humoral immunity, quantitation of virus-specific memory B cells (IgA, IgM and IgG + B cells) etc. This is a significant contribution to vaccine research in the country. During the Covid-19 pandemic, the platform was instrumental in generating scientific evidence for the T-cell immunity to Covid-19 vaccines and supporting the policy making for vaccine implementation. When the vaccine efficacy studies were not feasible, this platform was instrumental in conducting the immuno-bridging phase 3 clinical trial under industry-academia partnership for testing intranasal COVID- 19 vaccine “iNCOVACC” in generating the systemic and mucosal cell-mediated immunity (CTRI/2022/02/039992). The platform was also used for the interchangeability trial of Japanese encephalitis vaccines. Moreover, the tools are now available for evaluating the dengue vaccine candidates for their ability in inducing the long term and good-quality humoral immunity.