On 11/11/21 one of our core positions Gritstone Bio (GRTS) reported highly anticipated data from its CORAL COVID-19 vaccine program in non-human primates (NHPs). After scrupulous review and comparison between similar data sets for market leaders Moderna (MRNA) and Pfizer/BioNTech (BNTX), we remain confident that GRTS’s novel Chimpanze Adenovirus (ChAd) and Self-amplifying-mRNA (SAM) vaccine platform is capable of fulfilling the gap left by first-generation COVID-19 vaccines. For a refresher on this gap, you can read about it here in the “Embarrassment of T Cell Riches” report.
Rhesus macaques were protected against the COVID-19 challenge after homologous Prime/Boost (SAM/SAM), heterologous Prime/Boost (ChAD/SAM),or a single Prime jab (ChaD only). This observation held true across all combinations and dose levels explored (3, 10, 30 ug SAM and 5×1011 VP ChAd). Importantly, GRTS achieved the humoral (antibodies) and cellular (T cells) immune responses in NHPs equivalent to or better than first-generation mRNA vaccines at considerably lower doses (ChAd/SAM 30 ug and SAM/SAM 10 ug regimens appeared the most efficacious). In other words, 30 ug of SAM after Priming with ChAd OR two 10 ug SAM doses elicited the same or greater immune response than 30 ug or 100 ug two-dose series of the PFE/BNTX and MRNA vaccines, respectively. These are the doses that the vaccines were ultimately approved for. Of significance is that the homologous SAM/SAM vaccine can be manufactured more efficiently than first-gen mRNA vaccines at the same scale since lower volumes are needed. Another point of excitement lies with the potential for refrigerator stability of homologous SAM vaccination circumventing cold chain requirements, a major limitation for the global COVID-19 vaccine rollout.
GRTS’s novel ChAd/SAM vaccines compares favorably on efficacy to mRNA-1273 and BNT162b2 in NHPs
Data from the NHP studies presented in this report can be viewed here:
Of note, these studies were not designed or powered for direct comparison so any analysis doing so should be taken with a grain of salt.
Binding antibodies (IgG) lock onto viral surface proteins alerting the immune system to an infection. mRNA vaccines encode for bits of these proteins prompting the humoral immune system to generate antibodies capable of recognizing and binding to them. As we see in Figures 1, 3, and 3 above (MRNA, GRTS, and PFE/BNTX, respectively) the GRTS homologous and heterologous vaccination regimens produced similar levels of binding antibodies as the MRNA vaccine and greater levels than the PFE vaccine. Specifically, we see that at the 10 ug dose for MRNA there were over 8000 Geometric Mean Titers (GMT) compared to 10 ug and 30 ug SAM homologous doses (13000 and 8000, respectively). The heterologous ChAd/SAM regimen elicited greater levels at over 16K GMT. While the MRNA 100 ug generated IgG over 36K GMT it did so at more than 3X the dose. Looking at the PFE/BNTX NHP data set we see even a single dose of the GRTS ChAd vaccine-elicited more IgGs than two doses of BNT162b2 100 ug (~2600).
After recognition by IgG neutralizing antibodies (nAB) come in and prevent the virus from entering and infecting cells. They do this by binding to elements of the virus that block it from interacting with host cells. The free-floating virus can then be targeted and destroyed by the cellular arm of the immune system (i.e. T and B cells). In Figures 1, 3, and 3 above (MRNA, GRTS, and PFE/BNTX, respectively) we see that the GRTS regimens performed exceptionally well across the board compared to the MRNA and PFE/BNTX vaccines at stimulating potent nAB titers. Similar to IgG the homologous SAM/SAM 10 ug dose and heterologous ChAd/SAM 30 ug dose performed the best. When evaluating the nAB response with the Pseudovirus Neutralization Assay (PNA) or the Microneutralization assay (MNA) the GRTS platform outperformed the PFE/BNTX and MRNA vaccines in NHPs. For reference, the highest NT50 titers elicited by two doses of the PFE/BNTX and MRNA vaccines in NHPs were 1862 and 1689, respectively. Even one dose of GRTS’s ChAd vaccine was comparable if not better than its peer’s two-dose vaccines, especially when looking at results from the Microneutralization Assay.
While antibodies lock directly onto the virus outside of host cells T cells detect cells that have been infected. Once the virus penetrates a cell it hijacks the cellular machinery to replicate and produce its own viral proteins. Bits of these proteins (peptides) are presented on the surface of the host cell and are recognizable by peptide-specific CD8+ T cells. As the COVID-19 pandemic has progressed it become increasingly clear these specific T cells (also called memory T cells) are of great importance for long-term protection.
Immunity conferred by antibodies wanes over the span of months and certainly years. T cells, though, remain vigilant for decades as we have seen in SARS and MERS. Furthermore, data reported on yesterday (11/10/21) in the Guardian from a study following healthcare workers during the first wave of the pandemic presented compelling evidence that this applies in COVID-19 as well. Among the participants with high exposure risk 58 did not test positive for the virus. Researchers argued its because they had T cell immunity from previous infections with seasonal coronaviruses (i.e. the flu). That suggests that GRTS’s pancoronavirus vaccine aspirations are more than possible.
Turning to the data we see that the GRTS regimens shined in terms of T cells. While NHPs in all three studies had detectable levels of type-1 helper CD4 T cells (Th1) there were no CD8 T cells in the MRNA study. Minimal levels were detected in the PFE study but there was no mention of interferon-gamma (IFN-γ), a cytokine produced by CD8+ T cells, whereas the GRTS platform showed robust levels of IFN-γ. Another noteworthy publication on 11/11/21 in ScienceDirect highlighted that the minimal T cell response elicited by the PFE/BNTX vaccine was maintained in study subjects while antibodies diminished. Lastly, GRTS vaccines shined with regards to CD4+ T cells and cytokine IL-4 production.
Working together antibodies and T cells enable the body to clear out infected cells and viral particles from the airways. To measure the effectiveness of vaccines at training the immune system to do so investigators look for detectable levels of subgenomic RNA in the lungs (via Bronchial airway fluid samples), mouth (oropharyngeal), and nose (nasal).
In the GRTS study, we see vaccination with ChAd/SAM and SAM/SAM 10 ug arguably does a better job at this when considering BAL samples. On day 3 after the challenge, there was NO detectable COVID-19 subgenomic RNA at these two doses compared to 100% in control macaques compared to 13% in the MRNA study. By day 7 there was no RNA detectable at any dose level/combo among the GRTS regimens. This also compares favorably with the PFE/BNTX data where 33% of BNT162b2 vaccinated macaques were positive for RNA at day 3 compared to 55% in its control.
Looking at data from nasal swabs we see similar trends across the three studies. In the GRTS study by day 3, there was complete viral clearance in all doses/combos except for one compared to 40% in the controls. In the MRNA study, there was a 25% and 13% positivity rate at day 4 compared to 75% in its control. PFE data was more in-line with GRTS data showing complete clearance on day 3 compared to 56% in its controls. With regards to oral swabs, we only analyzed data for GRTS which appeared favorable. Although, it does seem that PFE/BNTX measured this too.
In conclusion, we look forward to clinical data from the GRTS booster study being conducted in the UK in 1Q22, as well as data from the NIH sponsored study in 1H22. Furthermore, GRTS should begin dosing patients in the South Africa study supported by $20M in funding from The Coalition for Epidemic Preparedness Innovations (CEPI). In our view, this preclinical data was another significant derisking event for the company and its infectious disease program. Especially considering how well the NHP efficacy data for MRNA and PFE/BNTX translated in humans.
I am/we are long GRTS