The Hunt for a Pan-Coronavirus Vaccine

Coronaviruses patently cause destructive pandemics, and it is possible that we will experience another one in our lifetimes. It makes sense to prepare a vaccine for possible future outbreaks, or for new variants of SARS-CoV-2.

In 2002, an epidemic of severe acute respiratory virus (SARS) broke out in China, killing one in ten of the >8,000 people it infected. In 2012, Middle East respiratory syndrome (MERS) was discovered to be a coronavirus in camels that occasionally infects people. In 2018, a man who traveled from Kuwait was diagnosed with MERS in Korea, resulting in 186 cases, including 38 fatalities. There are also indications that a late 19^th century pandemic involved a circulating coronavirus, OC43, rather than influenza. This virus still causes common colds today, and is a possibly underappreciated cause of mortality in the elderly too.

After SARS, scientists began investigating the origins and natural reservoirs of such viruses, reporting on Chinese horseshoe bats with SARS-like viruses, some of which were able to use the ACE2 receptor expressed in humans. Yet, in December 2020, when the initial reports of a new disease surfaced in China, the world had no coronavirus vaccine on hand. “After the SARS outbreak, we lost interest and failed to complete development of a vaccine for use in case of a recurrent outbreak. We must not make the same mistake again,” scientists at the National Institute of Allergy and Infectious Diseases (NIAID) noted in a commentary early in the pandemic. Now, researchers, vaccine developers and science funders are preparing, striving to develop vaccines that can protect against multiple species of coronaviruses.

“There’s an idea now that we should be prepared for something that we don’t know about but that could emerge,” says Professor Pamela Bjorkman, virologist at the California Institute of Technology in Pasadena. “We’ve had three epidemics or pandemics in the past 20 years from beta-coronaviruses that have zoonotic [animal] sources: SARS-1, MERS and SARS-2.” Vaccine experts are doubtful that we can develop a vaccine for all coronaviruses, but the beta-coronavirus genus will be an obvious first target, since this is the one recent out-breaks belong to. There are also two “common cold” coronaviruses that are in the beta genus, so a universal coronavirus vaccine might protect against them.

Multiple fronts

Multiple research groups have accepted the challenge to develop such a vaccine. In September, the NIAID announced an award of $36.3 million for three academic institutions to conduct research to develop vaccines that protect against multiple types of coronaviruses and viral variants. “These new awards are designed to look ahead and prepare for the next generation of coronaviruses with pandemic potential,” said NIAID director Anthony Fauci in a news release.

One project at Duke University aims to provide a vaccine for beta-coronaviruses at the onset of a future pandemic. “We have been working on a HIV vaccine for over 15 years and it is a very difficult vaccine to make,” says Professor Barton Haynes, who is leading the new project at Duke. This has served as inspiration for a recent pan-coronavirus vaccine candidate based on part of the spike protein. Specifically, 24 segments of the receptor binding domain of the spike from SARS-CoV-2 were enzymatically attached to a protein nanoparticle from a bacterium. This experimental vaccine was reported to elicit antibodies that neutralized bat coronavirus, SARS-CoV-2, the original SARS and two pandemic variants.

We compared it to mRNA vaccines designed just like Pfizer and Moderna vaccines, says Haynes, and it induced higher titers of antibodies and hit the then variants (alpha and beta) better. Haynes is optimistic that this vaccine could protect against all SARS-like viruses, including the omicron variant. Even though sequences of amino acids in the spike vary amongst coronaviruses in the beta genus, “there is a spot on the receptor binding domain that is common to all of them, and we showed that we are inducing those kinds of broadly reactive antibodies for this particular group,” he explains. Also added to the vaccine was an immune-boosting adjuvant consisting of alum and an agonist for a receptor that triggers frontline immune cells. Their Nature paper reported on an outstanding antibody response against SARS-CoV-2 in monkeys. “Our goal is to generate a second-generation vaccine that will neutralize all SARS-CoV-2 variants that might arise over the next three years to end the pandemic,” Haynes explains.

Variants add impetus

In California, Bjorkman is working on a vaccine for beta-coronaviruses that also relies on multiple receptor binding domains. “We’ve put a mixture of RBDs [receptor binding domains] on a single nanoparticle, which we call a mosaic RBD nanoparticle,” she explains. “The hope is that it would specifically trigger antibodies that are cross-reactive, so it wouldn’t matter if you didn’t include a particular strain.” A hypothesis is that these antibodies will recognize more conserved regions shared across viruses. Bjorkman is trying out her vaccine candidate in transgenic mice with human ACE2 receptors, in hamsters and on non-human primates.

The threat of new variants of concern has given the field extra impetus. “For a while, everyone said it is okay, we have a vaccine, we don’t need another one, but then when the variants arose, that kind of talk stopped,” recalls Bjorkman. She is collaborating with  Professor Alain Townsend’s group in Oxford to develop the nanoparticles, and a company in Scotland together with the UK’s Centre for Process Innovation, to produce a clinical grade version of the vaccine, with just one receptor binding domain – for now. Bjorkman’s work on mosaic nanoparticles was already advanced, before the pandemic, as she had worked on this as a strategy for a new influenza vaccine and for a potential HIV vaccine.

Another project at Brigham and Women’s Hospital seeks to discover more durable pan-coronavirus immunity by focusing on a region of the S2 part of the spike protein. This part does not bind to the cell – that’s the job of S1 – but rather, helps fuse the virus to it. Meanwhile, the receptor binding domain is on the S1 subunit and is a critical target for neutralizing antibodies.  

Another recent study identified human antibodies that cross-react with a part of S2 and inhibited beta-coronaviruses. The researchers proposed that, though difficult, lessons for such natural antibodies could facilitate the development of a broad beta-coronavirus vaccine. “I don’t think we have exhausted the potential of the spike as a vaccine target,” says Professor Duane Wesemann, who was not involved in this study. Wesemann’s team at Brigham has found that recalled immunity from prior coronavirus infections is linked to faster healing and greater durability of antibodies after recovery from COVID-19.

He points to our incomplete knowledge of antibodies to the SARS-CoV-2 virus and adds that “we don’t understand all the features that regulate whether an antibody response is going to be long lived or short lived”. Part of the goal of his research is to better understand the immune response to the virus and thereby uncover how to develop a longer lasting and broader response to beta-coronaviruses.

Wesemann’s work will create a perturbation matrix to turn up and down different controllable aspects of coronavirus vaccines, such as the interval between dosing, administration route, whether to use multiple strains in one vaccine or different strains sequentially and the impact of an immune-boosting adjuvant. In this way his lab will answer some basic questions on what alters the breadth and durability of an antibody response to coronaviruses. “Could we give SARS-CoV-2 as a prime [jab] and follow up with a MERS boost? And would that induce an immune response that is effective against them all, including another coronavirus that we didn’t use in our vaccine?” asks Wesemann.

T cells

Antibodies generated by B cells are not the whole story when it comes to our immune system fighting off viral infections. CD4 helper T cells are necessary to facilitate this antibody response, while CD8 killer T cells terminate infected cells. Designing vaccines that activate T cells is yet another route towards a pan-coronavirus vaccine.

Researchers in London previously looked at healthcare workers that tested negative for SARS-CoV-2 via PCR  and never developed neutralizing antibodies to the virus. Their evidence suggested that these people naturally resisted infection via T cells, which prevented  the virus from setting up an infection. The T cells spotted internal replication of the virus (infected cells display bits of viral proteins on their surface, tutoring T cells to recognize and destroy such cells). This tutoring might have happened due to coronavirus infections prior to SARS-CoV-2 emerging, noted Dr. Leo Swadling, study author at University College London.

This could be used to develop a T cell coronavirus vaccine, the researchers say. It could provide longer-lasting immunity and stop the virus earlier, said Professor Mala Maini, also at UCL. It might prove useful for pan-coronavirus T cell vaccines because internal proteins tend to be less variable than the spike proteins on the outside of the virus envelope. “The T cell response is thought to be wider, and more cross reactive across all coronaviruses, including alpha-coronaviruses,” explains Wesemann.

Other coronaviruses
 

Although the beta-coronavirus genus is the priority target of pan-coronavirus vaccines, the alpha genus are not forgotten; two human coronaviruses – 229E and NL63 –  are endemic in people and cause common cold symptoms, belong to this genus. Some suspect that when these viruses first infected humans, they too caused pandemics. Moreover, all of these endemic coronaviruses are increasingly associated with more severe illnesses than just a common cold.

“If we were successful in achieving a vaccine against the beta-coronavirus family, that would be a great success, and we would try and expand it across to the alpha [group],” says Wesemann. Moreover, finding out how to elicit a broader immune response against multiple coronaviruses could also feed into improved COVID-19 vaccines that could take on future variants of concern.

“There are several ways to work towards a broadly protective coronavirus vaccine,” concludes Dr. Thomas Gallagher, virologist at Loyola University Chicago. Even the mRNA or viral vector vaccines could follow some of these strategies outlined above.