Embarrassment of T Cell Riches

Eighteen months ago a new species of coronavirus now widely known as COVID-19 sent the world into disarray. Markets plunged as the global economy came to a grinding halt so that governments could blunt the trajectory of the rapidly spreading and evolving virus. In the United States alone there have been >36M reported cases, ~600K of which ended in death (and counting). American biotech companies in partnership with US government agencies, namely the National Institute of Health (NIH) and Biomedical Advanced Research and Development Authority (BARDA), swiftly initiated clinical testing of therapeutics and vaccines.

Although therapeutics played a crucial role early in the pandemic, and continue to do so, it’s the vaccines that have proved the most remarkable. In particular, the mRNA vaccine platforms which until recently were largely unproven. Among the ~100 companies globally with COVID-19 vaccine programs, only 11 have earned emergency use authorization (EUA). In the US there are only three: Moderna (MRNA), Pfizer (PFE)/BioNTech (BNTX), and Johnson and Johnson (JNJ) (viral-based). The key advantages (figure 1) of mRNA vaccine platforms over conventional protein or viral-based vaccines are 1) greater efficacy, 2) quicker to develop, and 3) increased manufacturing flexibility.

Figure 1: Source: MRNA Vaccine Day Presentation

At the outset investors and healthcare professionals alike were rightly skeptical that a safe and effective COVID-19 vaccine could be developed in a year (traditionally takes 5-10 years). MRNA and PFE/BNTX did it in even less time with JNJ not far behind. The reason that MRNA and PFE/BNTX were able to develop their vaccines so quickly is because of the aforementioned benefits of mRNA technology. What’s even more impressive is that the companies were able to do it without sacrificing efficacy or safety. In their respective P3 studies the MRNA and PFE/BTNX mRNA vaccines (2-doses ~3 weeks apart)) were 94% and 95% effective, respectively, at preventing infection with COVID-19. JNJ impressively achieved an 85% efficacy rate with a single dose of its viral-based vaccine.

The real-world data appeared to align quite well with the clinical data, that is until the delta variant emerged. The issue is that after 6-12 months COVID-19 antibodies begin to wane. T-cells on the other hand, specifically CD8+ memory T cells, remain vigilant for decades as we’ve learned from plasma samples from individuals who recovered from SARS in 2003. Thus, it’s no surprise that MRNA and PFE/BNTX have been pushing for EUA for their booster vaccines (and even got approval on 8/12/21 for the immunocompromised). Meanwhile, Gritstone Bio (GRTS) in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID) is quietly advancing its next-generation heterologous (viral + self-amplifying-mRNA) Prime (viral)/Boost (sa-mRNA) COVID-19 vaccine and booster. Data to date suggests that GRTS’s heterologous vaccine confers the same advantages outlined in figure 1 in addition to generating a robust CD4+/CD8+ T-cell (naïve and memory/cytotoxic) response unmatched by any platform. In our view, GRTS will start to get its COVID-19 program priced in once more data emerges. 

Early Validation of GRTS Platforms

In 2019, GRTS reported initial P1 data in cancer patients demonstrating “unprecedented levels of primed CD8+ neoantigen-specific cytotoxic T cells and expansion of pre-existing T cells even in low-dose cohorts”. President and CEO of GRTS Dr. Andrew Allen characterized the results as “important de-risking data”. We agree given that the premise of GRTS’s heterologous Prime (virus)/Boost (sa-mRNA) strategy is that switching vectors induces a robust T cell assault against specific antigens (short proteins on the surface of cancerous and infected cells). Then in July of last year, additional P1b data in patients with advanced colorectal, GEA, and Lung cancer emulated this immunogenic response and even showed signs of clinical benefit. 

GRTS Platform Now Being Applied to Improve 1st Gen COVID-19 Vaccines

We argue that there is a gap left by 1st gen vaccines which only train the immune system to recognize the Spike protein. Scientist seem to agree that to beat COVID-19 we need a vaccine that provides humoral (antibody) protection against spike AND T cell-mediated immunity against other viral proteins. Such a vaccine could arguably defeat COVID-19 and protect against future coronavirus outbreaks. To this point, a study published August 17 in the journal Cell Reports showed that in mice an mRNA vaccine with Spike + Nucleocapsid antigens provided better protection than Spike only. Specifically, researchers saw that the Spike only vaccine conferred acute protection in the lungs but not the brains of mice. Whereas the Spike + Nucleocapsid-based vaccine protected against breakthrough infection and provided acute protection in the lungs and brain. 

Based on compelling clinical data in cancer and preclinical data in non-human primates (NHPs) we believe that GRTS’s heterologous vaccine and/or booster could play a major roll in ending the pandemic and protecting against new ones. Importantly, the need for such a vaccine is even starker in immunocompromised individuals undergoing cancer therapy, organ transplants and the elderly. As we saw earlier this year in his testimony before the senate Dr. Fauci seems to be of this mindset that there is room for improvement: 

“NIAID researchers analyzed the immune responses of individuals who recovered from COVID-19 prior to the emergence of variants and demonstrated that T cells – a key component of the immune response to SARS-CoV-2 – were also capable of recognizing the three most widespread SARS-CoV-2 variants, B.1.1.7, B.1.351, and P1”

“On March 25, 2021, NIAID launched a Phase 1 clinical trial in healthy adults to assess the safety and immunogenicity of second-generation COVID-19 vaccine candidates developed by Gritstone Oncology, Inc. Gritstone’s COVID-19 vaccine candidates utilize a strategy aimed at inducing both neutralizing antibodies and T cell responses to elicit a broad immune response. This approach could provide protection against emerging SARS-CoV-2 variants by targeting several viral antigens, all of which are highly conserved among viral strains.”

Real-world data, including breakthrough infections, suggests MRNA and PFE vaccines wanes and are less effective against the Delta variant

More than six months since Dr. Fauci testified about the potential need for a vaccine such as GRTS’s his fear seems to have materialized with the delta variant. A few weeks ago the CDC reversed its stance on masks with many states reimposing mask mandates and other countermeasures to blunt the trajectory of the rapidly spreading delta variant. A recent pre-print study of hospitalization data collected at the Mayo Clinic investigated the efficacy of the MRNA and PFE/BNTX vaccines against the Alpha and Delta variants. 

Researchers performed a retrospective analysis of patients admitted with PCR confirmed COVID-19. The vaccines maintained exceedingly high efficacy profiles at preventing infection by the Alpha variant (85% and 76%, respectively). This dropped considerably against the Delta variant (to 76% and 42%, respectively) (table-1). Scientists that developed the MRNA and PFE/BNTX vaccines, as well as other key opinion leaders, agree that antibody protection will diminish over the coming months and years.

Unfortunately, though, with boosters developed using the same technology we are stuck playing whack-a-mole every time a new variant emerges which is looking more likely with the delta variant replicating rampantly (more replicating= more opportunities for mutations). That’s where a viral primed, sa-mRNA boosted vaccine like GRTS’s that can target more than just the Spike protein differentiates itself, as Dr. Fauci discussed. 

While the first-gen vaccine’s efficacy against early variants was impressive, Delta and other variants of concern are proving more challenging. You or someone you know have likely heard of fully vaccinated people receiving a positive Covid-19 test recently (breakthrough case). On August 2, 2021, Lindsey Graham made headlines after becoming the Senate’s first “breakthrough case”. While the Senator was fortunate enough to have mild symptoms and was glad to have the first-gen vaccine as the first line of defense, the trend appears to be intensifying.

Delta was estimated to represent 83% of COVID cases on July 20 in the U.S. and is having a ripple effect in hospitalizations amongst younger age groups. To get a better idea of Delta’s potential impacts, many experts have been assessing data from India and the U.K. The nearly twice as transmittable variant which was first detected in these two regions in December has largely been attributed to the monstrous spikes in cases and hospitalizations. India quickly became the epicenter of the pandemic after breaking records with multiple days of >400,000 recorded daily cases. Soon after India’s spike, the U.K. followed, nearing its January peak. During the recent spike, concerned observers were quick to point out the countries near 70% vaccination rate and high uptick occurring during warmer months. Experts are looking back to these upticks as a delayed impact appears to unfold in the U.S. and other regions. 

Similar to the U.K. and India, countries with relatively high vaccination rates are beginning to show concerning upticks in infections and hospitalizations. Iceland has 71.5 % fully vaccinated at the time of this writing. Israel 59.7% fully vaccinated and the U.S. 50.9% fully vaccinated (source: Our Word in Data)

Unfortunately, we still have a lot to learn about the Delta and other variants. With the majority over 80% of infections attributed to Delta, data is beginning to be tracked on breakthrough cases. General breakthrough infections are yet to be properly tracked, but the trend in hospitalizations amongst fully vaccinated people provides us with an early data point.     

Thankfully the majority of breakthrough cases appear to be mild and infrequently end in the ICU for now. While the likelihood of severe infection is currently low, the statistics are rapidly changing. Concerning metrics experts are paying close attention is the spike in admissions of younger age groups. Just months ago it was outlandish to see breakthrough cases, now it is increasingly becoming commonplace. As first-gen vaccines efficacy continues to wane and variants of concern continue to emerge, the need for a viral primed, sa-mRNA boosted vaccine which is capable of targeting more than just the Spike protein is becoming actively validated through real-world data. Source: The New York Times

GRTS’s heterologous vaccine-elicited robust antigen-specific CD4+/CD8+ (cytotoxic and naïve) T cells in NHPs relative to convalescent plasma and other mRNA vaccines. Moreover, this was observed in cancer patients adding confidence that the effect translates in humans.