Nathaniel Jackson, a research assistant with the emerging infectious disease branch at the Walter Reed Army Institute of Research, studies coronavirus protein samples last year. The branch is part of the institute’s effort to produce a COVID-19 vaccine candidate. Army photos by Mike Walters
SILVER SPRING, MD — At Walter Reed Army Institute of Research, flexibility has been the watchword of the last 18 months. The team at WRAIR pivoted quickly from other work to focus on developing a vaccine for SARS-CoV-2 as soon as the scientific community had access to the full genome in January 2020. In addition to the challenges of understanding and learning how to combat the novel coronavirus, the researchers needed to figure out how to conduct small-scale production with the Pilot Bioproduction Facility in the midst of a multi-year renovation.
Now, their flexibility has taken on new meaning. The vaccine they developed has the potential to adapt to more situations than any to date. In animal testing, it provoked a strong immune response to SARS-CoV-2—and the Alpha, Beta, and Gamma variants.1 It also appears to induce a potent antibody response to SARS-CoV-1, the version of the coronavirus responsible for the Severe Acute Respiratory Syndrome (SARS) that emerged in late 2002 and spread to more than two dozen countries, killing 10% of those infected before petering out in early 2004.
The goal is to develop a pan-coronavirus vaccine that would protect against the eight coronaviruses known to sicken humans and others that arise in the future. That includes four that cause the common cold as well as Middle Eastern Respiratory Syndrome (MERS), which jumped from camels to humans in 2012 and spread to 27 countries. With a 35% mortality rate but limited human-to-human transmission, MERS continue to occur sporadically today.
The latest coronavirus, CCoV-HuPn-2018, was first isolated in 2021 from a sample taken from a Malaysian child who developed pneumonia in 2017-2018. The finding occurred in the course of developing a diagnostic test that could identify multiple types of novel coronaviruses and led to the retrospective identification of seven additional cases in the same city. That virus appears to be a novel canine-feline recombinant alphacoronavirus.2
New Variants, New Viruses
The WRAIR researchers are keenly aware of the need for broad protection against SARS-CoV-2 variants, given the rapid spread of the Alpha variant that came to dominate in the U.S. this spring and the even more contagious and more lethal Delta variant that appears likely to overtake it in the next few weeks. They also knew that the challenge extended beyond this pandemic and known coronaviruses.
“Even before recent COVID-19 variants were identified, our team was concerned about the emergence of new coronaviruses in human populations, a threat that has been accelerating in recent years,” said Kayvon Modjarrad, MD, director of the Emerging Infectious Diseases Branch (EIDB) at WRAIR who leads the Army’s COVID-19 vaccine research efforts and co-invented the vaccine with WRAIR structural biologist Gordon Joyce, MD, of the Henry M. Jackson Foundation for the Advancement of Military Medicine. “That’s why we need a vaccine like this: one that has potential to protect broadly and proactively against multiple coronavirus species and strains.”
The vaccine’s potential applicability to multiple viruses arises from its novel approach. The Pfizer-BioNTech and Moderna vaccines use mRNA to deliver instructions for the production of proteins that trigger an immune response to SARS-CoV-2 and the Johnson & Johnson vaccine relies on an adenovirus technology to transport similar instructions for protein creation. The WRAIR vaccine eliminates the instruction and protein creation steps by directly presenting the spike protein characteristic of coronaviruses on a very virus-like engineered nanoparticle.
“We have designed and positioned this platform as the next generation vaccine, one that paves the way for a universal vaccine to protect against not only the current virus, but also counter future variants, stopping them in their tracks before they can cause another pandemic,” Modjarrad said.
The vaccine, called spike ferritin nanoparticle (SpFN), has spikes that cover a polymerized 24-faced ferritin platform (think soccer ball). Ferritin occurs in nearly all living organisms. The unique shape enables the nanoparticle to present the same spike protein repeatedly, potentially generating a stronger immune response, or to mix up the presentation to cover variants or different coronaviruses.
Retooled Facilities
While WRAIR’s Clinical Trial Center has conducted more than 150 clinical trials of drugs and vaccines, the SpFN study faced unusual challenges because the facility used to produce the small batches needed for studies was out of commission.
The Pilot Bioproduction Facility (PBF) has been operational for nearly 70 years and was in acute need of updating. The timing for renovations didn’t account for a pandemic, however, meaning the staff and contractors found themselves pressed to wrap up construction and undertake all the steps needed to meet good manufacturing processes of an acutely accelerated schedule because there was no other option.
“The PBF fills a crucial need in a very important part of the vaccine production pipeline – Phase 1, or ‘first off the bench,’ production suitable for Phase 1 clinical trials,” explained Rick Millward, WRAIR PBF associate director. “Although this is a required step in this process, the availability of independent facilities willing to manufacture a full range of Phase 1 production under one roof is extremely limited.”
Getting the facility in order required calibration and aqualification of equipment and development of a manufacturing process for the new vaccine. “Even outside a pandemic, there’s very little room for error when manufacturing vaccines. While we were working as quickly as possible, we also had to ensure our facility, processes and products were manufactured effectively,” said Maj. Jeffrey Froude, director of the WRAIR PBF.
The PBF team pulled together to get the work done and the vaccine prepared, with the first doses produced in December 2020. A placebo-controlled phase 1 clinical trial of the vaccine began in April with 72 healthy adult volunteers aged 18 to 55 years.
- Joyce MG, Chen WH, Sankhala RS, et al. SARS-CoV-2 ferritin nanoparticle vaccines elicit broad SARS coronavirus immunogenicity. Preprint. bioRxiv. 2021;2021.05.09.443331. Published 2021 May 10. doi:10.1101/2021.05.09.443331
- Vlasova AN, Diaz A, Damtie D, et al. Novel Canine Coronavirus Isolated from a Hospitalized Pneumonia Patient, East Malaysia [published online ahead of print, 2021 May 20]. Clin Infect Dis. 2021;ciab456. doi:10.1093/cid/ciab456