Development of simpler immunotheraputics

National Institute On Aging

Investigators

Linked publications & trials

Abstract

1, To develop simpler and safer COVID-19 vaccine strategy, we utilized the technology developed in my laboratory, such as to enhance immunogenicity of peptide fragments via expressing them on the surface of viral empty particles. For this purpose, we generated a chimeric gene that encodes receptor-binding domain (RBM) of SARS-CoV2 virus fused with HBsAg gene. Although expression of this chimeric gene supposed to expose RBM on the surface of HBsAg particles (thus enhance its immunogenicity), we failed to generate a tangible amount of anti-RBM or SARS-CoV2-specific antibody. We therefore abandoned this vaccine strategy and utilized an alternative approach to enhance immune responses via a targeted-deliver of antigens to antigen-presenting cells. Our new vaccine expresses RBM linked to viral chemokine, vMIP2. I now report that this vaccine, vMIP2-RBM, elicits high levels of antibody specific to RBM, RBD, and S1 antigen of SARS-CoV2 in mice. Surprisingly, the vaccine response was superior to that of protein-based vaccines, implying that we have devised a unique and highly effective vaccine strategy. At present, we are further modifying this construct to include T-cell epitopes of SARS-CoV2. Our aim is to devise vaccine that elicits both virus neutralizing antibody and T cell responses. Overall, the study is progressing as planned, and SARS-CoV2 virus neutralizing assays will be performed soon. We are about to establish this assay in the laboratory. 2. People with Down syndrome suffer from increased risk and complications from respiratory infections, including COVID-19. They also exhibit cognitive decline, which is linked to a life-long overexpression of the APP and DYRK1A genes and consequent overproduction of neurotoxic A and hyperphosphorylation of Tau in the brain. In my recent opinion articles co-written with DS experts (Illouz et al., Neuromolecular Med. 2021; and Illouz et al. Front Immunol. 2021), I have emphasized importance and urgent need for vaccines to protect DS people from COVID-19 as well cognitive decline. Here I report that my collaborative efforts with professor Okun, Bar-Ilan University, Israel, have led to successful validation of this idea that the DS-associated cognitive decline can be effectively reversed via immunization with A-expressing vaccine. Consistent with my previous efforts that improved cognitive impairments in mice with Alzheimers disease (Olkhanud et al, Vaccine, 2011), we now show that immunization of mice with DS can efficiently decrease accumulation of neurotoxic A in the brain and reverse cognitive decline. We also demonstrate that DS mice can be protected from A-associated complications if maternally immunized. Overall, we have successfully completed the study. Our results, which we recently published (Illouz et al., Communications Biol., 2021; and Illouz et al, Vaccine. 2021), imply that wellbeing of humans with DS can be improved by eliciting immune responses to potentially harmful antigens accumulated in the brain. 3. We recently found that a hypothetical peptide derived from epididymis can differentially deliver antigens into cytosol of dendritic cells and CD8 T cells. It appears that this peptide has high affinity to CD8 T cells, indicating that it may act via yet unknown cell surface receptor. Unfortunately, due to COVID19 pandemic, we temporarily halted efforts to characterize and clone this hypothetical receptor. However, we continued a second part of the project - its use to modify function of CD8 T cells. The strategy is based on our in house-developed and patented chemoarp technology that can deliver immune regulatory siRNA/miRNA into T cells (Biragyn et al., J. Immunotherapy, 2013). Here, I hypothesize that our hypothetical epididymis (EP)-derived peptide may allow us to modify function of CD8 T cells by delivering immune modulatory oligonucleotides and antigens. To test this idea, we produced and purified EP peptide fused with recombinant antigen (Ag) by expressing it in yeast. Subsequent tests indicate that EP-Ag can be uptaken and thus, modify function of CD8 T cells. Overall, the study is progressing as planned. We aim to complete it and publish results in 2022. This high-risk project further enforces my original idea that function of immune cells can be modulated to elicit desired responses at will. I believe that the strategy will have significant translational value.