LONDON—PepTC Vaccines Ltd., a subsidiary of Treos Bio Ltd., recently shared positive preclinical results of its investigational PolyPEPI-SCoV-2 peptide vaccine. The research was published on bioRxiv and has been submitted for peer-reviewed publication.
The study reports that the PolyPEPI-SCoV-2 vaccine was safe in two mouse models and elicited highly specific, TH1-biased CD8+ and CD4+ T cell responses against all four structural proteins of the SARS-CoV-2 virus. Vaccination induced humoral responses, as measured by total mouse IgG for BALB/c and human IgG for CD34+ humanized mouse models.
Dr. Eniko R. Toke, chief scientific officer of Treos Bio and corresponding author of the study, tells DDN that “PolyPEPI-SCoV-2 contains nine fragments derived from all four major structural proteins of the virus, aiming to induce broad memory T cell responses in each individual with a similar diversity as COVID-19 convalescent individuals do, thus mimicking the immune cell repertoire that is generated when a natural infection occurs.”
“We anticipate that in case of viral infection, elevated numbers of diverse CD8+ effector T cells generated from memory pools established by vaccination will recognize and kill the infected cells, the place where the virus replicates. Eliminating viral reservoirs in the early-stage of SARS-CoV-2 infection, before a high viral load [could] be generated, would prevent illness in the immunized individual and block onward transmission to other people,” notes Toke.
“However, achieving multiple T cell targets in each individual and at the same time in the whole population is challenging, as T cells are known to be highly variable among individuals themselves—it may be the reason for the tendency to ‘ignore’ them by vaccine developers,” she says. “Genetic differences (e.g., the HLA genotype regulating T cell responses) are well known to contribute to individual variations in the immune response to pathogens. Evidence is also continuing to emerge that the COVID-19 pandemic could be disproportionately affecting people from Black, Asian and minority ethnic communities. The proprietary technology of PepTC used to design PolyPEPI-SCoV-2 [will] address this issue.”
The study shows that PolyPEPI-SCoV-2 defines natural CD8+ and CD4+ T cell responses observed in asymptomatic or mild COVID-19 patients one to five months after symptom onset. In tests of blood samples from 17 donors, the PolyPEPI-SCoV-2-specific CD8+ T cell repertoire was very diverse. Donors recognized an average of seven different vaccine peptides out of nine, and 87 percent of donors had multiple vaccine-specific T cells against three SARS-CoV-2 structural proteins; 53 percent had T cells against all four.
PepTC believes that long-term control mediated by T cells is unlikely when only the spike of the virus is targeted.
“Despite 87 percent of subjects having CD8+ T cells against S protein, we found that S-specific memory T cells represented only 36 percent of the convalescents’ total T cell repertoire detected with vaccine peptides; the remaining 64 percent was distributed almost equally among N, M and E proteins,” adds Toke. “Across the donors, the breadth and magnitude of immune responses did not change with time from disease onset, suggesting the presence of long-term memory T cells.”
“[O]ur approach has two main differentiating factors. First, we are using very extensive T cell epitopes beyond the Spike, which makes the vaccine robust to viral mutations, enhancing the likelihood of long-lasting immunity,” she continues. “Second, we have used our proprietary technology to select the right peptides to generate robust CD8+ T cell responses in both the individual and the whole population, independent of ethnicity, by taking into consideration different HLA genetic backgrounds.”
Peptide-based vaccines have had limited success to date, due in part to the lack of knowledge regarding the selection of immunogenic peptides. The authors of the paper argue that this uncertainty is reduced by understanding of how an individual’s genetic background responds to specific peptides.
“To the best of our knowledge, PolyPEPI-SCoV-2 is the first vaccine candidate whose potential immunological efficacy could be pre-assessed with precision, since the HLA-genotype of convalescent donors predicted their peptide-specific T cell responses, with 84-percent accuracy (confirming our computational approach based on HLA-genotype data of real subjects). Data extrapolated to 16,000 HLA-genotyped US subjects of 16 different ethnicities estimate a 98-percent global coverage independent of ethnicity,” Toke explains. “PolyPEPI-SCoV-2 will generate meaningful immune responses in all human populations (including BAME populations) that would not be achieved using the current state-of-art epitope selection approaches, widely proposed for COVID-19 vaccine development purposes.”
According to Toke, “This is a major advance in vaccine development that we believe will change the world of vaccine effectiveness and utility. [W]e have good reasons to believe that we will have a vaccine that will have excellent therapeutic longevity, measured in many years. The platform provides the flexibility to analyze changes in the virus and easily change the peptide cocktail over time if needed, to ensure that we are always providing the most effective vaccine at any given time. This could overcome the challenges observed with influenza vaccines.”
PepTC has obtained pre-IND regulatory confirmations from the FDA, the Medicines & Healthcare products Regulatory Agency of the U.K., and Germany’s Paul Ehrlich Institut.
“Clinical testing and preparation for the large-scale manufacturing are the next main tasks. The relatively simple nature of the drug substance peptides in the proposed vaccine means that bespoke manufacturing facilities will not be required to manufacture product at scale, and the vaccine is stable for storage without requiring special temperature conditions. The technology to manufacture can be readily transferred to multiple existing GMP facilities located throughout the world, to deliver the billions of doses required,” says Toke. “We are currently in the process of raising the money required to finance our Phase 1 and Phase 2 programs. We plan to start [a] Phase 1/2 study early next year.”
PepTC expects to have preliminary trial results in the spring of 2021.