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T.The first HIV drug brought dying patients back from the brink. But as enthusiastic doctors rushed to bring the wonder drug to new patients, the miracle dissolved. In each patient, the drug only worked for a while.
It turned out that the drug was very good at killing the virus, but the virus was also better at developing resistance to the drug. A spontaneous mutation in the genetic material of the virus prevented the drug from doing its job, and so the mutant viruses were able to replicate wildly despite the drug, making patients ill again. It took another decade for scientists to find evolution-proof therapies.
Could the same thing happen to a COVID-19 vaccine? Could a safe and effective vaccine in initial trials fail because the virus evolves to get out of trouble? As evolutionary microbiologists who have studied a poultry virus that has developed resistance to two different vaccines, we know that such an outcome is possible. We also think we know what it takes to stop it. COVID-19 vaccines may fail, but if they have certain properties, they won’t.
History of vaccine resistance
For the most part, humanity has been lucky: most human vaccines have not been undermined by microbial evolution.
For example, the smallpox virus was eradicated because it never found a way to evolve around the smallpox vaccine, and no measles virus strain has ever emerged that can beat the immunity triggered by the measles vaccine.
But there is one exception. A bacterium that causes pneumonia has managed to develop resistance against a vaccine. Developing and replacing that vaccine with another was expensive and time-consuming, with seven years between the initial emergence of resistant strains and the licensing of the new vaccine.
There have been no other failures for human vaccines yet, but there are indications that viruses, bacteria and parasites may or are evolving in response to vaccination. Escape mutants that are able to evade vaccine-induced immunity are routinely seen in the microbes that cause hepatitis B and whooping cough.
For human diseases such as malaria, trypanosomiasis, influenza and AIDS, vaccines have been difficult or impossible to develop because the microbes that cause those diseases evolve so quickly. In agricultural settings, animal vaccines are often undermined by viral evolution.
How would it be?
If SARS-CoV-2 evolves in response to a COVID vaccine, there are several directions it could take. The most obvious is what happens with the flu virus. Immunity works when antibodies or immune cells bind to molecules on the surface of the virus. If the mutations in those molecules on the surface of the virus change, the antibodies cannot cling to them so tightly and the virus is able to escape. This process explains why the seasonal flu vaccine needs to be updated every year. If this happens, a COVID vaccine needs frequent updates.
But evolution could go in other directions. It would be better for human health, for example, if the virus evolved invisibly, perhaps reproducing slowly or hiding in organs where immunity is less active. Many pathogens that cause barely noticeable chronic infections have taken this tactic. They avoid detection because they do not cause acute illness.
A more dangerous path would be if the virus developed a way to replicate faster than the immunity generated by the vaccine. Another strategy would be for the virus to target the immune system and dampen vaccine-induced immunity.
Many microbes can survive inside the human body due to their exquisite ability to interfere with our immune system. If SARS-CoV-2 has ways to even partially disable human immunity, a COVID vaccine could favor mutants who do it even better.
Evolution-proof vaccines
Before COVID came along, the two of us compared vaccines that continue to work with vaccines that have been weakened by the evolution of pathogens.
It turns out that truly evolution-proof vaccines have three characteristics. First, they are very effective in suppressing viral replication. This interrupts further transmission. No replication, no transmission, no evolution.
Second, evolution-proof vaccines induce immune responses that attack different parts of the microbe at the same time. It is easy for a single part of the virus to mutate and escape the target. But if many sites are attacked at the same time, immune escape requires many separate escape mutations to occur simultaneously, which is nearly impossible. This has already been demonstrated in the laboratory for SARS-CoV-2. There the virus rapidly developed resistance to antibodies targeting a single site, but struggled to develop resistance to a cocktail of antibodies, each targeting multiple different sites.
Third, evolution-proof vaccines protect against all circulating strains, so no one else can fill the void when competitors are removed.
Will a COVID vaccine be evolution-proof?
About 200 COVID vaccine candidates are at various stages of development. It is too early to know how many of them have those evolutionary proof characteristics.
Fortunately, we don’t have to wait for a licensed vaccine to not find out. A little more effort during vaccine trials can go a long way in determining whether a vaccine will be evolution-proof. By dabbing people who received the experimental vaccine, scientists can tell how far levels of the virus are suppressed. By analyzing the genome of any virus in vaccinated people, it may be possible to see evolutionary fugue in action. And by taking blood from the vaccinated, we can calculate in the laboratory how many sites of the virus are attacked by vaccine-induced immunity.
Clearly, the world needs COVID vaccines. We believe it is important to pursue those who will continue to work. Probably, many candidates in the current portfolio will. Let’s find out what clinical studies are and let’s follow them. Vaccines that provide only temporary relief leave people vulnerable and take time and money to trade. They can also cancel other vaccines if viruses resistant to multiple vaccines evolve at the same time.
Today the world has insecticide-resistant mosquitoes and crop pests, herbicide-resistant weeds, and a crisis of antibiotic resistance. There is no need for history to repeat itself.
Andrew Read is the professor of biology and entomology at Evan Pugh University and director of the Huck Institutes of the Life Sciences at Penn State. His team works on virulence and infectivity, adaptation to new hosts, vaccine failure, and resistance to drugs and insecticides.
David Kennedy is an assistant professor of biology at Penn State. Research in the Kennedy lab focuses on gaining a mechanistic understanding of disease ecology that can be used to understand the evolution of pathogens. Find David on Twitter @ dkenned11
A version of this article was originally posted in Conversation and has been republished here with permission. The conversation can be found on Twitter @ConversationUS
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