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Relatives attend the funeral of a COVID-19 victim in Manaus, Brazil, on January 13.
PHOTO: MICHAEL DANTAS / AFP / GETTY IMAGES
When the number of COVID-19 cases started to increase again in Manaus, Brazil, in December 2020, Nuno Faria was amazed. The virologist at Imperial College London had just written an article in Science estimate that three-quarters of the city’s inhabitants had already been infected with SARS-CoV-2, the pandemic coronavirus – more than enough, it seemed, for the development of collective immunity. The virus must be done with Manaus. However, hospitals were filling up again. “It was difficult to reconcile these two things,” says Faria. He started looking for samples he could sequence to find out if changes in the virus could explain the resurgence.
On January 12, Faria and colleagues posted their initial findings on virological.org. Thirteen of the 31 samples collected in mid-December in Manaus ended up being part of a new viral strain that they called P.1. Much more research is needed, but they say one possibility is that, in some people, P.1 avoids the human immune response triggered by the lineage that devastated the city in early 2020.
Emerging variants of the coronavirus have been on the news since scientists raised the alarm about B.1.1.7, a variant of SARS-CoV-2 that first caught the attention of scientists in England in December and is more transmissible than previously circulating viruses (Science, January 8, p. 108). But now, they are also focusing on a new potential threat: variants that could wipe out the human immune response. These “immune breakouts” may mean that more people who have had COVID-19 remain susceptible to reinfection and that proven vaccines may, at some point, need an update.
At a meeting of the World Health Organization (WHO) on January 12, hundreds of researchers discussed the most important scientific questions raised by the wave of new mutations. WHO also convened its Emergency Committee COVID-19 on January 14 to discuss the impact of the new variants and the travel restrictions that many countries are imposing to contain them. The committee called for a global effort to sequence more SARS-CoV-2 genomes to help track mutations.
The most transmissible variant, B.1.1.7, is already spreading rapidly in the UK, Ireland and Denmark, and probably in many other countries. But scientists are also concerned about 501Y.V2, a variant detected in South Africa. Some of the mutations it carries, including the so-called E484K and K417N, alter its surface protein, peak, and have been shown in the laboratory to reduce how well monoclonal antibodies fight the virus. In a preprint published earlier this month, Jesse Bloom, an evolutionary biologist at Fred Hutchinson Cancer Research Center, showed that E484K also reduced the potency of convalescent serums from some donors by 10 times – although he is quick to add that this does not necessarily mean the mutation would cause people’s immunity to the new strain to drop 10 times.
P.1 raises concerns because it appears to have reached a similar constellation of mutations and appeared in a location with a high level of immunity. “Whenever you see the same mutations coming up and starting to spread over and over again, in different viral strains around the world, it’s really strong evidence that there is some evolutionary advantage to these mutations,” says Bloom.
Like B.1.1.7, the Brazilian variant is already in motion. When Faria was finishing his analysis of Brazilian genomes, a report was published of a variant detected in travelers arriving in Japan from Brazil – and it ended up being P.1. (Like Science went to print, US researchers also reported several new variants, but their importance has remained unclear.)
LIKE THESE NEW the variants are affecting the course of the pandemic is unclear. In Manaus, for example, P.1 may have nothing to do with the new outbreak of infections; people’s immunity may simply be declining, says Oxford University epidemiologist Oliver Pybus. Or it may be driving the increase because it is more easily transmitted, like B.1.1.7, not because it can escape the immune response. “Of course, it could also be a combination of these factors,” says Pybus.
Likewise, in a recent modeling study, researchers at the London School of Hygiene & Tropical Medicine calculated that South Africa’s 501Y.V2 variant could be 50% more transmissible, but no better at escaping immunity, or as transmissible as the previous variants, but able to escape immunity in one in five previously infected people. “The reality can be between these extremes”, wrote the authors.
Ester Sabino, a molecular biologist at the University of São Paulo, São Paulo, launched a study to find reinfections in Manaus that could help decide between these hypotheses for P.1. Laboratory studies investigating the variants are also underway. The United Kingdom launched on January 15 a new consortium, G2P-UK (from “genotype to phenotype-UK”), led by Wendy Barclay of Imperial College London, to study the effects of emerging mutations in SARS-CoV-2. An idea discussed at the WHO meeting on 12 January is the creation of a biobank that will assist studies by housing virus samples, as well as plasma from vaccine containers and recovered patients.
The interactions between the new mutations can make it more difficult to detect their effects. The UK, South Africa and Manaus variants share a mutation called N501Y, for example, or Nelly, as some researchers call it. But the mutation, which affects the spike protein, also occurs in some variants that don’t spread faster, suggesting that the N501Y doesn’t operate alone, says Kristian Andersen of Scripps Research: “Nelly can be innocent, except maybe when she’s dating your bad friends. “
Bloom believes that none of the changes will allow the virus to escape the immune response entirely. “But I would expect these viruses to have some advantage when a large part of the population has immunity” – which may help explain the increase in Manaus.
UP TO THE VIRUS it does not appear to have become resistant to the COVID-19 vaccines, says vaccinologist Philip Krause, who chairs a WHO working group on COVID-19 vaccines. “The not-so-good news is that the rapid evolution of these variants suggests that if it is possible for the virus to evolve into a vaccine-resistant phenotype, it could happen sooner than we would like,” he adds. That possibility adds to the urgency of putting good surveillance in place to detect such leakage variants from the start, says University of Florida biostatistics Natalie Dean.
People line up for the COVID-19 vaccine in Birmingham, UK
PHOTO: JACOB KING / PA WIRE / BLOOMBERG / GETTY IMAGES
Some scientists fear that the proposed changes in vaccine dosing regimens may accelerate the evolution of these strains. Desperate to tame a large increase in cases, the United Kingdom on December 30 decided to allow up to 12 weeks between the first and the second dose of two authorized vaccines, instead of the 3 or 4 weeks used in clinical trials of the vaccines, then more people can get their first dose quickly and have at least some immunity. And the Trump administration decided to dispatch all available doses immediately, instead of withholding 50% to ensure that people received their second dose in time. That policy, which the Biden administration said it will follow, may inadvertently extend the dosage interval if future vaccine deliveries do not arrive or are not delivered on time.
Widespread delays in the second dose can create a pool of millions of people with enough antibodies to slow the virus and prevent illness, but not enough to eliminate it. This could very well be the perfect recipe for creating vaccine-resistant strains, says virologist Florian Krammer of the Icahn School of Medicine at Mount Sinai: “If we end up with everyone receiving just one dose with no doses available for timely reinforcement, that would be in my opinion, it is a problem. “
But others say that the uncontrolled spread of the virus poses greater risks. “It’s a carnage out there,” says evolutionary microbiologist Andrew Read of Pennsylvania State University, University Park. “Twice as many people with partial immunity have to be better than full immunity for half of them.” Historically, few viruses have managed to develop resistance to vaccines, with the notable exception of seasonal flu, which evolves so quickly on its own – without the pressure of the vaccine – that it requires a new vaccine designed each year.
If vaccine-resistant strains of SARS-CoV-2 appear, vaccines may need to be updated. Several vaccines can be easily changed to reflect the most recent changes, but regulators may be hesitant to authorize them without seeing the updated safety and efficacy data, says Krause. If new variants circulate with the older strains, multivalent vaccines, effective against several strains, may even be necessary. “To be clear: these are later considerations,” says Krause. “The public should not think that this is imminent and that new vaccines will be needed.” But Ravindra Gupta, a researcher at the University of Cambridge, says manufacturers should start producing vaccines designed to generate immunity to mutant versions of the spike protein, because they keep coming. “It tells us that we must have these mutations in our vaccines, so that you can close one of the pathways for the virus to fall.”
For now, increasing transmissibility is the biggest concern, says virologist Angela Rasmussen of Georgetown University. “I am intrigued why [that] it is not an important part of the conversation, ”she says. The US hospital system, she says, “is crowded in many places and further increases in transmission can push us to the limit where the system collapses. Then we will begin to see potentially huge increases in mortality. “