Substantial progress has been made by the MassCPR Vaccines Working Group. Most groups collaborated extensively with other groups within MassCPR. The work performed contributed to two major vaccines that were approved by FDA (Moderna, Johnson & Johnson) as well as multiple other vaccine platforms. The work has resulted in multiple publications in high impact journals, but more limited new IP.
The proposals can be grouped in 3 different areas:
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Novel vaccine candidates and vaccine platforms (Walker, Vanderberghe, Knipe)
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Evaluation of adjuvants (von Adrian, Levy, Chen, Murray)
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Immune responses to SARS-CoV-2 infection and approved COVID-19 vaccines (Wesemann, Harrison, Barouch, Benoist, Elledge, Moon)
Novel Vaccine Candidates and Vaccine Platforms
Bruce Walker and colleagues employed a new approach known as structure-based network analysis to define highly conserved and mutation-resistant regions across SARS-CoV-2 and the subgenus of coronaviruses from which SARS-CoV-1 and SARS-CoV-2 originated. A cell-based assay was developed to comprehensively identify T cell targets within the mutation-resistant regions and their immunogenicity was confirmed in COVID-19 patients. These conserved T-cell antigens are now incorporated into the Codiak Biosciences exosome-based vaccine.
Luk Vanderberghe and colleagues generated and evaluated in animal models a vaccine based on the adeno-associated viral vector (AAVrh32.33) expressing the SARS-CoV-2 Spike protein. A number of IND-enabling studies have been completed, particularly on the CMC side and studies to demonstrate the efficacy of the vaccine. Initial dialogue with the FDA has been started and regulatory consultants have been engaged. Studies were performed to address specific concerns that the Agency has raised. In parallel, regulatory discussions for an ex-US Phase 1 study are being pursued. Finally, companies such as Novartis have been engaged and have agreed to manufacture the vaccine for clinical studies.
David Knipe and colleagues explored herpes simplex virus type 1 (HSV-1) vectors expressing the SARS-CoV-2 Spike and Nucleocapsid proteins. They developed vectors and demonstrated immunogenicity in mice. They also used the HSV-1 vectors to study inflammatory responses in tissue culture.
Evaluation of Adjuvants
Uli von Adrian and colleagues studied the ability of bisphosphonate (BP) to increase potency of COVID-19 vaccines (Adeno, mRNA, and protein+ CPG). The von Andrian group was able to show that the widely prescribed oral BP, alendronate, can increase neutralizing and cellular responses of the Moderna COVID-19 vaccine (mRNA-1273) when delivered SC concomitantly with the vaccine in mice.
Ofer Levy and colleagues used the RBD domain of SARS-CoV-2 Spike to evaluate in young and old mice multiple pattern recognition receptor (PRR) agonists formulated with alum. They found that an AH and CpG adjuvant formulation (AH:CpG) produced robust immunogenicity and protected mice from the SARS-CoV-2 challenge. Furthermore, they discovered that AH:CpG can activate older human leukocytes in vitro. Finally, they found that Carbohydrate fatty acid Mono-Sulphate derivative (CMS) induces the highest SARS-CoV-2 neutralization in aged mice when adjuvanting a RBD-nanoparticle vaccine.
Jianzhu Chen and colleagues evaluated enhanced mRNA-based vaccines with lymph node-targeted delivery by modified lipid nanoparticles. They also evaluated a neutralizing antibody-inducing adjuvant using Toll-like receptors.
Megan Murray and colleagues evaluated BCG as a strategy to prevent SARS-CoV-2 and other respiratory virus infections in humans. Studies were planned in the US but encountered multiple hurdles and were not implemented due to insufficient funding. Studies were initiated in Taiwan.
Immune Responses to SARS-CoV-2 Infection and Approved COVID-19 Vaccines
Duane Wesemann and colleagues evaluated the human antibody response to SARS-CoV-2 in both naturally infected as well as vaccinated individuals. They studied both serum antibody responses as well as B cell responses and defined major antibody competition groups. They showed that sustained antibody responses tend to occur in people with broad immunity to other coronaviruses. They showed that cross-variant breadth may be superior by natural immunity compared to vaccine immunity.
Stephen Harrison and colleagues collaborated with Wesemann by evaluating the cryo-EM structures of monoclonal antibodies described above. They charted escape by SARS-CoV-2 variants. The results led to a global atlas of S-specific memory B-cell repertoires.
Dan Barouch and colleagues developed a macaque model of SARS-CoV-2 infection and demonstrated the protective efficacy of both natural and vaccine immunity. They determined mechanistic correlates of protection using adoptive transfer and CD8 depletion strategies. They contributed to the development of the Johnson & Johnson vaccine and studied in humans the magnitude and durability of the Pfizer, Moderna, and J&J vaccines.
Christophe Benoist and colleagues evaluated the T cell response to SARS-CoV-2. They defined CD8 T cell epitopes and corresponding T cell receptors, and evaluated perturbations of Treg responses.
Steve Elledge and colleagues analyzed SARS-CoV-2 antibody responses using VirScan that can identify virus-specific epitopes in a highly multiplexed format. They developed VirScan epitope libraries for all coronaviruses and showed cross-reactivity and patterns of severity.
James Moon and colleagues developed peptide:MHCII tetramer reagents for immunology studies and provided these reagents to the MassCPR community.
