The hunt for the pan-coronavirus vaccine

Coronaviruses obviously cause destructive pandemics, and we may experience another in our lifetime. It makes sense to prepare a vaccine for possible future epidemics or for new variants of SARS-CoV-2.

In 2002, a severe acute respiratory virus (SARS) epidemic broke out in China, killing one in ten of the more than 8,000 people infected. In 2012, Middle East Respiratory Syndrome (MERS) was discovered to be a coronavirus in camels that occasionally infects humans. In 2018, a man from Kuwait was diagnosed with MERS in Korea, which resulted 186 cases, including 38 fatalities. There are also indications that at the end of the 19and pandemic of the century involved a circulating coronavirus, OC43, rather than influenza. This virus still causes common colds today and is also a perhaps underestimated cause of death in the elderly.

After SARS, scientists began to investigate the origins and natural reservoirs of these viruses, realized that 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 first reports of a new disease surfaced in China, the world did not have a coronavirus vaccine on hand. “After the SARS epidemic, we lost interest and failed to complete the development of a vaccine to be used in the event of a recurring epidemic. We must not make the same mistake again,” said scientists from the National Institute of Allergy and Infectious Diseases (NIAID) noted in a comment at the start of the pandemic. Now researchers, vaccine developers and science funders are gearing up, striving to develop vaccines that can protect against multiple species of coronavirus.

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

Several facades

Several research groups have accepted the challenge of developing such a vaccine. In SeptemberNIAID announced a price $36.3 million to three academic institutions to conduct research to develop vaccines that protect against multiple types of coronaviruses and virus variants. “These new awards are designed to anticipate and prepare for the next generation of coronaviruses with pandemic potential,” NIAID Director Anthony Fauci said in a statement. Press release.

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

We compared it to engineered mRNA vaccines like the Pfizer and Moderna vaccines, Haynes says, and it induced higher antibody titers and hit 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 the amino acid sequences in the spike vary among beta-genus coronaviruses, “there is a spot on the receptor-binding domain that is common to all of them, and we have shown that we induce these types of antibodies largely reactive for this”. particular group,” he explains. An immune-boosting adjuvant consisting of alum and an agonist of a receptor that triggers first-line immune cells was also added to the vaccine. Their Nature paper reported an exceptional antibody response against SARS-CoV-2 in monkeys. “Our goal is to generate a second-generation vaccine that will neutralize all variants of SARS-CoV-2 that may arise over the next three years to end the pandemic,” says Haynes.

Variations add momentum

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

The threat of worrying new variants has given the field an extra boost. “For a while everyone said it was okay, we have one vaccine, we don’t need another one, but when the variants came out, that kind of talk stopped,” recalls Bjorkman. She collaborates with the teacher Alain Townsend’s group in Oxford to develop the nanoparticles, and a company in Scotland working with the UK’s Center for Process Innovation to produce a clinical-grade version of the vaccine, with a single receptor-binding domain – for now. Bjorkman’s work on mosaic nanoparticles was already advanced, before the pandemic, because she had worked on them as a strategy for a new flu vaccine and for a potential HIV vaccine.

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

Another one recent study identified human antibodies that cross-react with part of S2 and inhibit beta-coronaviruses. Researchers offers that, while difficult, the lessons for such natural antibodies could facilitate the development of a broad beta-coronavirus vaccine. “I don’t think we’ve exhausted the potential of the spike as a vaccine target,” says Professor Duane Wesemann, who was not involved in this study. by Wesemann Brigham’s team found that Recalled immunity against previous coronavirus infections is linked to faster recovery and greater durability of antibodies after recovery from Covid-19.

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

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

T cells

Antibodies generated by B cells are not everything for our immune system which fights viral infections. CD4 helper T cells are needed to facilitate this antibody response, while CD8 killer T cells terminate infected cells. Design vaccines that activate T cells is yet another route to a pan-coronavirus vaccine.

Researchers in London have previously examined healthcare workers who tested negative for SARS-CoV-2 via PCR and never developed neutralizing antibodies against the virus. Their testimonials suggested that these people naturally resisted infection via T cells, which prevented the virus from triggering an infection. T cells have spotted the internal replication of the virus (infected cells display fragments of viral proteins on their surface, prompting T cells to recognize and destroy these cells). This tutoring may have happened due to coronavirus infections before to the emergence of SARS-CoV-2, Noted dr. Swaddled Leoauthor of the study 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 sooner, noted Professor Mala Maini, also at UCL. This could prove useful for pan-coronavirus T-cell vaccines because internal proteins tend to be less variable than spike proteins outside the virus envelope. “The T-cell response is thought to be broader and more reactive on all coronaviruses, including alpha-coronaviruses,” says Wesemann.

Other coronaviruses

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

“If we were successful in obtaining a vaccine against the beta-coronavirus family, it would be a great success, and we would try to extend it to the alpha family. [group]“, explains Wesemann. Additionally, discovering how to elicit a broader immune response against multiple coronaviruses could also fuel improved Covid-19 vaccines that could take on worrying future variants.

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

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