Brazil Must Now Contend With Two SARS-CoV-2 Variants

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Just over 20 days after Japan’s National Institute of Infectious Diseases announced the detection of a new SARS-CoV-2 variant — isolated from samples from four travelers from Amazonas, Brazil — the P.1 variant has already been detected in multiple other countries besides Brazil and Japan, from the United States to Germany to the Faroe Islands, according to a World Health Organization (WHO) report.

“Now we can say that P.1 is not only in Manaus,” Felipe Naveca, PhD, vice-director of research at Fiocruz Amazônia, told Medscape Medical News.

“We sequenced some 100 samples in 13 municipalities in the state of Amazonas and in 11 of them we found P.1 circulating,” he said. He added that in December, the prevalence was 51%, and by January 13, it had increased to 91%.

“We are going to increase the number of municipalities even more and sequence samples from Rondônia,” Naveca added.

A first case of infection by P.1 had already been documented in the United States — in a Minnesota resident with a history of travel to Brazil — and three cases in São Paulo were announced January 26 by the State Health Department of São Paulo.

“It is expected,” Naveca said. “When detected, the virus has been circulating for some time.”

The emergence of P.1 probably occurred between November and December 2020, and the new strain’s spread appears to be rapid. There are still no data, but the Fiocruz Network is studying random samples from different times throughout the country.

In addition, researchers are monitoring the emergence of a second variant, called P.2, identified in Rio de Janeiro.

In the case of Manaus, researchers led by Naveca confirmed a trend recently announced by the Brazil-United Kingdom Center for Discovery, Diagnosis, Genomics and Epidemiology (CADDE), which includes researchers from the University of São Paulo.

Ester Sabino, MD, PhD, and her team released preliminary results of an analysis of samples from 48 tests in Manaus between January 1 and 9. Of the 48 samples, most (85.4%) were the P.1 variant. The authors highlighted that, although preliminary, the rate was already substantially higher than the 52% of samples with the P.1 variant (from 67 patients in Manaus) detected in the last 2 weeks of 2020.

Viruses such as SARS-CoV-2 change. Of the hundreds of variants already detected in the first year of the pandemic, the ones that most concern scientists — the so-called variants of concern (VOCs) — are those originating in the United Kingdom, South Africa, and P.1 in Brazil.

The small differences in viral genetic material can offer advantages, such as being more transmissible or evading antibodies (whether produced by a previous infection or stimulated by vaccination). In the case of the Amazonian P.1 variant, the molecular structure of the microorganism indicates it has both these advantages. Was P.1 then the cause of the chaotic situation in the northern part of the country in Manaus?

“We don’t know if the complicated epidemiological situation in Manaus was the cause of the rise of the P.1 line, or if the P.1 line was what led to this health chaos. But if it starts to be found in other places and has the same effect observed in Manaus, of overlapping the other strains, that would already be a strong indicator that it is more transmissible,” Tiago Gräf, PhD, told Medscape Medical News. Gräf is a biomedical researcher at Instituto Gonçalo Moniz, from Fiocruz, focusing on ​​evolution and the molecular epidemiology of viruses.

Gräf pointed out that the number of COVID-19 cases has also increased in Rio de Janeiro where, until now, the P.1 line hadn’t been detected.

“It may be that the increase in cases is a consequence of the end-of-year parties, the beach, holidays, crowds, tiredness, euphoria with the vaccine, which make the lineage more frequent,” he said. “We need to be monitoring.”

“We are trying to find out the path that the virus took within the state of Amazonas, but it has not yet been possible,” said Naveca. He added that the pace of the scientists’ work in the last several days has been a frenzied one: “The results of the tests left on Sunday (January 24), we analyzed everything between [the days right after], I shared with colleagues who are helping me with the phylogenetic analysis. We will try to understand it better, but we still don’t have that answer.”

Zeroing In on the Mutation

The presence of the N501Y mutation is what fuels the fear of greater transmissibility. There are no shortcuts to confirm whether a strain that has the mutation is or is no longer transmissible. It’s based on indirect evidence obtained through genomic surveillance, which identifies whether new strains replace old ones over time — which appears to be happening. Researchers also try to interpret the effects of mutations cataloged by viral genomic surveillance using computer modeling to assess whether a mutation improves the virus’ ability to interact with cells. But it is also not enough.

“In a little while, studies on transmissibility with animals will start to appear,” explained Gräf. “After infecting a mouse, it is necessary to see if they produce more viruses in the airways or if there is more infection in the lung.”

P.1 is also of concern because it carries other mutations, especially E484K, related to the reduced effect of neutralizing antibodies — which could then generate cases of reinfection and low immune responses to vaccines.

“We have already confirmed [a P.1 reinfection]. In fact, it was in one of the first samples that we sequenced,” Naveca said.

In vitro studies of whether a strain can evade the immune system are relatively simple. A strain is cultivated using serum from patients who have already been infected with SARS-CoV-2 and, therefore, have antibodies against the virus. Researchers measure how many cells the new strain can infect. If it can’t infect any, it means those patients’ antibodies are working to neutralize it. But there are still other unanswered questions.

Scientists still don’t know the severity of disease caused by the P.1 variant, Naveca said. They also don’t know which age group would be most affected. He told Medscape Medical News that he talked with many medical colleagues, and “some report that they see younger people, others think there is no big difference between age groups. We need to increase the number of analyses to apply statistical tests, because we are having conflicting opinions, and we need to be sure.”

Nor is there any certainty about whether the new strain would change the effectiveness of vaccines. WHO results on January 12 suggested that vaccines protect against the UK and South African variants, but P.1 has not yet been studied. Samples of the new strain have already been sent to Fiocruz in Rio de Janeiro to conduct studies on neutralization. According to Naveca, the teams there are working in real-time in partnership with vaccine manufacturers to get the results as quickly as possible.

Moderna and Pfizer have already presented results indicating their vaccines protect against the UK and South African variants. Still, in vitro tests to measure the antibody response don’t have the last word.

“This in vitro testing work must be done by everyone, manufacturers and researchers,” Sabino told Medscape Medical News. “Science needs many groups working to answer this question.”

“But it is logical that in vitro studies do not answer everything. In practice, it will be necessary to conduct clinical tests, follow vaccinated patients, verify that the rate and transmission of P.1 is the same in those who have not been vaccinated, and monitor the incidence of it in that region,” she said. “You may need to run tests with different vaccines to see which one has the best response to these variants.”

Pharmacuetical companies are already considering the possibility of booster doses or making adaptations to the formulations. Even with the prospect of reinfections and vaccines that may not protect against some strains, there is light at the end of the tunnel.

“It is hoped that the second infection or infection in a vaccinated person will not progress to severe COVID-19,” said Gräf. “Antibody immunity, even if reduced, and cellular immunity can still help, perhaps not preventing the person from becoming infected, but by decreasing the symptoms and amount of circulating virus, preventing the person from developing serious illness.”

P.2 and Other Variants

The E484K mutation is also present in another variant of Brazilian origin that has appeared in several states. This variant, informally called the “Rio de Janeiro” line, also has a new name: P.2.

The P.2 variant was announced in December, after being identified in Rio de Janeiro, Cabo Frio, Niterói, and Duque de Caxias, in Baixada Fluminense. It was also identified in different states in the northern part of the country and more recently in Rio Grande do Sul. In Amazonas, the P.1 variant is still predominant over P.2.

“From November until now, only one sample had P.2, against 60 that were from P.1,” explained Naveca. P.2, however, is still a concern due to its wide geographical distribution and because it carries the E484K mutation, which raises concern about reinfection and, perhaps, reduced vaccine efficacy.

“P.2 has the mutation that decreases response to neutralizing antibodies, but the number of mutations is smaller and does not seem to have taken the evolutionary leap that P.1 has taken,” Sabino said. “P.2 has not yet entered the VOC list, but apparently it has a different characteristic from the others, maybe it will end up on the list.”

“For now, it is still considered a strain that needs to be studied better,” she added.

The same week, two new strains of SARS-CoV-2 in southern Brazil were described and disclosed in two separate preprints. The new variants are not classified as VOC, “but we need to understand them better because new variants will appear all the time,” said Naveca.

Restrictive Measures

VOCs have revived debates at the beginning of the pandemic about closing borders — at the national, state, or municipal level. France is moving toward imposing restrictions, the UK is considering mandatory quarantines, Germany is studying canceling flights, and Australia has even suspended the air bubble it had with New Zealand. Since January 26, the United States has restricted entry of non-US citizens from Brazil.

Experts still debate strategies. Some see closures as necessary. Others believe it’s more important to have good virus sequencing programs to detect agile variants, as well as robust screening programs.

“I am concerned about discussing control measures in Manaus with the situation we are experiencing. There are patients who, if not transferred, can die. The only chance for some people is removal to other locations, and there is also a risk with asymptomatic people,” Naveca said.

“It is best to increase genomic surveillance and tracking, restrict unnecessary visits and travel, and meetings that do not need to be held in person,” added Gräf. “Governments should guide this.”

This article was translated and adapted from the Portuguese edition of Medscape.

Sabino, Naveca and Gräf have reported no relevant financial relationships.

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