Preclinical studies using a “future-proof” vaccine technology developed by researchers at the University of Cambridge have shown that just one antigen can be modified to provide a broadly protective immune response against different coronaviruses, and other viruses, in multiple animal models. The research, carried out by the team at the University, and its spinout, DIOSynVax (Digitally Immune Optimised Synthetic Vaccines), suggest that a single vaccine with combinations of these antigens could protect against an even greater range of current and future coronaviruses.

The new vaccine candidate is based on a single, digitally designed and immune-optimized antigen, designated T2_17, that is based on the receptor binding domaine (RBD) of the spike protein, and so targets a part of the virus that is required for replication. The team’s reported studies in mice, rabbits and guinea pigs found that their prototype vaccine candidate provided a strong immune response against all known variants of SARS-CoV-2, as well as other major coronaviruses, including those that caused the first SARS epidemic in 2002. First-in-man trials are now under way.

“Unlike current vaccines that use wild-type viruses or parts of viruses that have caused trouble in the past, this technology combines lessons learned from nature’s mistakes and aims to protect us from the future,” said research lead Jonathan Heeney, PhD, at Cambridge University’s Department of Veterinary Medicine. “These optimized synthetic antigens generate broad immune responses, targeted to the key sites of the virus that can’t change easily. It opens the door for vaccines against viruses that we don’t yet know about. This is an exceptionally different vaccine technology—it’s a real turning point.” The investigators published their preclinical findings in Nature Biomedical Engineering, in a paper titled “A computationally designed antigen eliciting broad humoral responses against SARS-CoV-2 and related sarbecoviruses.”

Among the coronaviruses of the greatest pandemic risk are the viruses of the Betacoronavirus genus that bind to angiotensin-converting enzyme 2 (ACE-2), the authors wrote. “Over the past two decades, two ACE-2-binding sarbecoviruses have spilled over into human populations, causing the severe acute respiratory syndrome (SARS) epidemic in 2002–2003 and the current SARS coronavirus 2 (SARS-CoV-2) pandemic. These ‘spillovers’ from animals to humans have highlighted the need for vaccines to provide broad-based protection. “Bats are a reservoir of a large number of SARS-CoV-like ACE-2-binding sarbecoviruses which pose a constant threat for future spillover into humans, with the potential to cause new epidemics,” the authors continued. And as Heeney noted, “In nature, there are lots of these viruses just waiting for an accident to happen.”

And, as the authors further pointed out, “In addition to the zoonotic spillover from the related bat or other mammal sarbecoviruses, another cause of concern is the rapid accumulation of immune-escape mutations in circulating SARS-CoV-2.” An accumulating number of variants of concern (VOCs) have implications for increased transmission and escape from natural and vaccine-induced immunity,” the team pointed out. “An ideal vaccine candidate targeting circulating and emerging VOCs would be a single antigen providing protection against the diverse group of sarbecoviruses.”

All currently available vaccines, such as the seasonal flu vaccine and existing COVID-19 vaccines, are based on virus strains or variants that arose at some point in the past. “However, viruses are mutating and changing all the time,” said Heeney. “Current vaccines are based on a specific isolate or variant that occurred in the past, it’s possible that a new variant will have arisen by the time we get to the point that the vaccine is manufactured, tested and can be used by people … We wanted to come up with a vaccine that wouldn’t only protect against SARS-CoV-2, but all its relatives.”

Heeney’s team has been developing a new approach to coronavirus vaccines, by targeting their “Achilles heel.” Instead of targeting just the spike proteins on the virus that change to evade our immune system, the Cambridge vaccine targets the critical regions of the virus that it needs to complete its virus life cycle. “All the current vaccines use the full-length spike as the antigen and only 16% of the antibodies generated against the spike antigen are RBD-directed,” the team noted. The team identifies these regions through computer simulations and selecting conserved structurally engineered antigens. “This approach allows us to have a vaccine with a broad effect that viruses will have trouble getting around,” said Heeney. “…  to increase the coverage to all the viruses of the Sarbecovirus subgenus of betacoronaviruses, we used a digitally immune-optimized synthetic vaccine (DIOSynVax) technology to design antigens,” the team explained in its paper. “These computationally immune-optimized and structurally engineered antigens are selected in vivo to induce immune responses across a group of related viruses.”

Using this approach, the investigators identified a unique antigen structure that gave broad-based immune responses against different Sarbecoviruses, the large group of SARS and SARS-CoV-2 related viruses that occur in nature. ““As T2_17 is an RBD-based antigen substantially differing from the Wuhan-Hu-1 strain of SARS-CoV-2, it could be used as a booster vaccine candidate for overcoming immune imprinting by vaccines that use the full-length spike.” The optimized antigen is compatible with all vaccine delivery systems: the team administered it as a DNA immunogen (in collaboration with the University of Regensburg), a weakened version of a virus (modified Vaccinia Ankara, supported by ProBiogen), and as an mRNA vaccine (in collaboration with Ethris). In all cases, the optimized antigen generated a strong immune response in mice, rabbits and guinea pigs against a range of coronaviruses.

Even though the vaccine was designed before the emergence of the Alpha, Beta, Gamma, Delta and Omicron variants of SARS-CoV-2, it provided a strong protection against all of these and against more recent variants, suggesting that vaccines based on DIOSynVax antigens may also protect against future SARS-CoV-2 variants. “All the studies combined indicate that T2_17 is an efficacious “single antigen for targeting multiple sarbecoviruses and support its applicability across different vaccine technologies,” the team wrote. “Immunization with T2_17 generated a robust humoral immune response against SARS-CoV, SARS-CoV-2, RaTG13, WIV16 and the SARS-CoV-2 variants Alpha, Beta, Gamma, Delta and Omicron (BA.1, XBB.1.5). That the design predated the emergence of these VOCs and none of the sequences were included in the initial design is a strong indication of the efficacy of the DIOSynVax technology.”

Based on a strong safety profile, first-in-human clinical trials are now ongoing at Southampton and Cambridge NIHR Clinical Research Facilities. The last booster immunizations will conclude by the end of September.

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