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Principal Investigator: Mark Connors
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2022
Award: $217,764
Funding agency: National Institute of Allergy and Infectious Diseases
Our laboratory is engaged in the study of the immune response to SARS-CoV-2 in two major areas. The first of these is the study of the immune response to natural infection. The second is the response to virus-like particles or replicating recombinant adenovirus type 4 (Ad4) vaccines.
We are collaborators on a large natural history study of up to 300 survivors of SARS-CoV-2 and their household contacts, led by Dr. Michael Sneller. In this study, serum and peripheral blood mononuclear cells are sampled during acute infection and over 3 years. Our laboratory will be primarily responsible for measuring the cellular immune response to SARS-CoV-2 gene products. A large panel of functions of T cells specific for SARS-CoV-2, including frequency, cytokine secretion, and cytolytic capacity, will be measured over time to examine the dynamics of frequency and functions, and the potential correlations with disease severity.
In a separate effort, a vaccine platform that is being developed for influenza virus and HIV has been repurposed to induce immunity against SARS-CoV-2. Over the past several years our section has developed several vaccine platforms for use as vaccines to present viral surface glycoproteins. Both replicating vectors and virus-like particles (VLPs) have proven to be highly immunogenic platforms in rabbit and human studies. After vaccination with Ad4 expressing influenza H5 Vietnam (Ad4-H5-Vtn), participants developed levels of neutralizing antibodies that were higher and more durable than those induced by the licensed Sanofi vaccine (Matsuda et al., Science Immunology, 2019). In addition, H5-specific B cell expansions, and neutralizing antibody hypermutation and potency, continued for 6-12 months after a single intranasal vaccination. The vaccine induced potent mucosal and systemic antibody responses. When tested at 3-5 years, the serum neutralizing antibody response was unchanged from the peak. Vaccinee responses could be increased to even higher levels by boosting with the licensed H5 vaccine. More recently, we have developed VLP platforms to present viral surface glycoproteins. For RSV, this platform has been shown to induce levels of neutralizing antibodies above those induced by RSV infection in small animals. In our work, we have been able to use VLPs to induce H5-specific neutralizing antibodies titers in rabbits of approximately 1:1000 after two immunizations.
The reason for the HSIS to pursue the COVID-19 spike protein is that most of the approaches being considered as vaccines against COVID-19 are not replicating vaccines and are not given intranasally. Of the currently licensed anti-viral vaccines, only two forms provide a sufficiently potent B cell stimulus that they confer lifelong immunity. These are live-attenuated viruses and virus-like particles. Over the past several years there has been great progress in understanding the immunology that underlies the success of these approaches. Both have the potential to present the nave B cell with viral surface glycoproteins in the appropriate conformation that approximates the disease-causing virus against which they protect. They can induce pro-inflammatory cytokines and contain TLR agonists that drive B cell responses. In addition, they are particulate in nature. There is very good experimental evidence that particulate immunogens are considerably more potent than other forms. The COVID-19 spike protein is immunogenic, relatively conserved, and with regard to immunogenicity, should behave similarly to stabilized RSV F or influenza H5. For these reasons, we feel that the more immunogenic replicating or VLP approaches will provide an important complement to other approaches being pursued.
Perhaps most important, the intranasal Ad4 platform offers the possibility to induce mucosal immunity on the upper respiratory tract. This immunity is not induced by vaccines given intramuscularly. In the case of poliovirus, local mucosal immunity on the GI tract has been critical to the interruption of transmission. In numerous small animal models, intranasal immunization has been shown to induce potent restriction in the upper airway of a SARS-CoV-2 challenge virus. This is true when intranasal vaccines were given alone, but even higher responses have been observed when intranasal adenovirus vaccines were used to boost responses to currently authorized vaccines in mice. It is likely that intranasal vaccination using the replicating Ad4 platform offers the possibility to induce potent mucosal immunity in humans and thereby play an important role in limiting the transmission of SARS-CoV-2.
This year we demonstrated that Ad4 can infect Syrian hamsters, one of the best animal challenge and transmission models. We then showed that intranasal immunization with Ad4-SARS-CoV-2 recombinants induced potent serum and mucosal antibodies. These candidates are being studied in the hamster challenge model and being prepared for clinical trials later this year.
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