The first generation of vaccines for Covid-19 is rolling out all over the world. But are these vaccines able to withstand the force of viral evolution?
The year 2021 has launched with a plethora of Covid-19 vaccines approved around the world. In Europe, candidates from AstraZeneca/University of Oxford, Moderna, and BioNTech/Pfizer are rolling out. The BioNTech/Pfizer vaccine in particular is showing signs of reducing Covid-19 cases in Israel, which has one of the most advanced vaccination programs in the world.
However, emerging Covid-19 variants are rearing their heads. These include the so-called UK and Brazilian variants, which are challenging vaccine efforts by spreading faster than previous strains. There could also be other variants of Covid-19 lurking in the population undetected by genomic screening.
Frontrunner vaccine developers have been quick to reassure that their vaccines continue to work against the main variants. But there were recent signs that the Oxford vaccine is less effective against a variant common in South Africa than against other strains, causing the country to halt the distribution of that vaccine. This raises the possibility that some approved vaccines won’t be able to fully protect against all Covid-19 strains.
A vaccine arms race is underway
When the coronavirus SARS-CoV-2 reproduces itself in cells, errors often appear in the copying process. Many such errors have no noticeable effects, but others can lead to changes in its structure and impact the way the virus infects humans.
“The more people infected with the virus, the more random mutations arise. Some of these mutations are beneficial to viral replication so they self-perpetuate,” said Thomas Rademacher, co-founder and CEO of the UK firm Emergex Vaccines. “It’s a game of chance that could be equated to rolling a die and getting a six. The more dice you roll, the higher the likelihood of getting a six.”
Most Covid-19 vaccines in the market and in development train the immune system to detect antigens on the surface of SARS-CoV-2. The most frequently used antigen is a protein called spike, which is seen as the most effective vaccine target. However, mutations to the spike protein underlie the main variants causing concern.
“The more people becoming infected or vaccinated, the higher the selection pressure on the spike antigen becomes. This makes the key target of the antibody response more subject to mutations,” said Alexandre Le Vert, Executive Chairman and co-founder of the French vaccine firm Osivax.
The slow rollout of vaccinations in some countries may give the virus time to mutate its spike protein and escape the vaccine. In time, some vaccines could even start to exacerbate Covid-19 infections via a phenomenon known as antibody-dependent enhancement, where certain antibodies stick to the virus incorrectly and end up contributing to the infection.
“We should expect more variants to appear regularly and we will most likely reach a situation similar to flu, where multiple variants will be circulating every winter season,” warned Le Vert.
The most advanced vaccine producers are beginning to take precautions against the threat of Covid-19 variants. Moderna is developing a booster dose to better tackle emerging SARS-CoV-2 strains. AstraZeneca recently said that it will take between six and nine months to produce vaccines effective against new strains. Meanwhile, the German biotech CureVac recently launched a €150M collaboration with GlaxoSmithKline to develop messenger RNA (mRNA) vaccines that could work against a wide range of Covid-19 variants.
Enter the universal Covid-19 vaccine
One way to circumvent the vaccine arms race is developing a universal vaccine that is future-proof against the evolving coronavirus. How might this work? According to Rademacher, a key clue lies in examining vaccines for other viral infections that have stayed effective for decades.
His company, Emergex, studied the effects of the yellow fever vaccine — a weakened form of the yellow fever virus — on the virus-busting abilities of immune T cells. Like Covid-19, yellow fever is caused by an RNA virus. Last year, the company revealed that after vaccination, T cells largely ignore the surface antigens of the yellow fever virus. Instead, they recognize antigens within the virus.
“Many of the vaccines currently being developed for Covid-19 are targeting surface proteins and particularly the spike [protein],” said Rademacher. “Our results suggest that this may not produce an equivalently safe, effective, and long-lived immune response compared to that seen with live attenuated vaccines.”
Few companies are developing live attenuated vaccines for Covid-19. Though they can provide very strong protection, these vaccines are tricky to transport and may be unsafe for people with weakened immune systems. Most developers have opted for other approaches such as inactivated vaccines, viral vectors, and mRNA vaccines.
If live attenuated vaccines are off the table, then how could other types of vaccines achieve long-lasting protection? Emergex is one of a number of vaccine developers setting their sights on T cells — a key part of our immune ‘memory’ for future infections — and internal SARS-CoV-2 antigens.
Biotech companies aiming inside SARS-CoV-2
In early January, Emergex launched a collaboration with the Institute of Technology on Immunobiologicals (Bio-Manguinhos) in Brazil. The partners aim to develop synthetic Covid-19 vaccines that mimic the internal SARS-CoV-2 antigens that T cells are able to detect on infected cells.
Osivax is using a similar approach, developing a vaccine candidate that consists of nanoparticles carrying copies of internal Covid-19 antigens.
“We believe that targeting internal antigens such as the nucleocapsid presents an advantage over surface antigens as they have a much lower mutation rate,” said Le Vert. He added that an immune T cell response against these internal antigens could protect against both current and future strains of Covid-19.
The company raised €32M in July last year to fund the development of the vaccine, which is expected to reach phase I trials within the next year. Additionally, the funding will allow Osivax to develop a vaccine capable of universal protection against flu — a virus that mutates far more rapidly than coronaviruses.
Another company going beyond the viral surface is the Belgian company eTheRNA. It is developing a vaccine made of mRNA molecules, like those of the German companies CureVac and BioNTech. The mRNA molecules deliver genetic instructions that cause the patient’s cells to produce the viral antigen. In this way, the vaccines can be manufactured without the complex production facilities needed for other vaccines.
Unlike CureVac and BioNTech, eTheRNA makes the patient’s cells produce a mix of SARS-CoV-2 antigens both on the surface and inside the virus. In addition to making the immune system produce antibodies, the vaccine activates T cells.
“The viral surface is more sensitive to mutation and strain drift – and an antibody-based approach is potentially vulnerable to such changes,” said Wim Tiest, eTheRNA’s Director of Infectious Disease Programme Strategy.
“That is why an approach like ours that targets a broader part of the virus and triggers a multi-angled immune response offers a valuable alternative despite the longer development timelines.”
Using the proceeds of a €34M Series B round closed in June last year, eTheRNA is developing the vaccine with the aim of entering phase I trials in early 2021.
A diverse Covid-19 vaccine arsenal
Out of the more than 200 Covid-19 vaccines in development worldwide, those of Emergex, Osivax, and eTheRNA are in a minority that target internal viral antigens. Other companies seem confident that vaccines against spike and other surface targets will protect over the long term, provided the proper booster shots are available.
“It is very difficult to actually predict when a ‘perfect’ escape variant will arise,” said Diane Van Hoorick, VP Translational Development at eTheRNA. “In response to mutational variants, next-generation vaccines with an alternative [spike] protein sequence could be implemented on an even shorter time track when building on the expertise gained already.”
Nevertheless, it seems prudent to build up a diverse range of vaccine technology that can provide long-term protection. Some think Covid-19 will become a part of life going forward. Additionally, pandemics of other types of viruses are inevitable in the future.
“The current situation highlights the need to move fast with diversity of new vaccines and new and adaptable vaccine technologies that have different courses of action, and that have the potential to deliver broader protection,” said Rademacher.
This is an updated version of an article first published on the 27th of August, 2020.
Images from Elena Resko and Shutterstock