The World Health Organization said on Monday that a SARS-CoV-2 variant circulating in India is of global concern.
“We classify it as a variant of concern at a global level,” Maria Van Kerkhove, WHO technical lead on COVID, told a briefing. “There is some available information to suggest increased transmissibility.”
India’s daily COVID statistics are down slightly but remain high. The health ministry said Monday there were 366 161 new cases and 3754 deaths from the virus in the previous 24-hour period. Public health experts believe the new cases and deaths to be an underestimate of the true picture.
India has 22.6 million COVID cases so far, according to the Johns Hopkins Coronavirus Resource Center. India’s case load is surpassed only by the US, with 32.7 million COVID cases.
There is also growing concern in India about ‘black fungus’ or mucormycosis, an opportunistic fungal infection which is affecting COVID patients and also those who have recovered from the disease. It typically only appears in immunocompromised patients. COVID patients with diabetes are particularly susceptible to mucormycosis, medical experts said. Meanwhile, struggling to contain its own COVID outbreak, Nepal is running short of oxygen and oxygen tanks and has asked Mount Everest climbers and guides not to abandon their oxygen cylinders on the mountain, rather bringing them back down so that medical facilities can fill them to give to COVID patients.
Kul Bahadur Gurung, a senior official with the Nepal Mountaineering Association, told Reuters, “We appeal to climbers and Sherpas [Himalayan people living around Nepal and Tibet, well known for climbing mountains] to bring back their empty bottles wherever possible as they can be refilled and used for the treatment of the coronavirus patients who are in dire needs.”
A Nepal health ministry official speaking to Reuters said the country needs 25 000 oxygen tanks immediately.
While Indian hospitals buckle under COVID cases and even capacity for cremations runs out, a new ‘double mutant’ variant of the virus has emerged.
First announced just one month ago, scientists are already trying to determine if it is driving the surge in Indian cases — and the implications for the rest of the world.
“We need to keep a close eye on this variant,” Katelyn Jetelina, PhD, MPH, of the University of Texas Health Science Center at Houston, wrote in a recent email newsletter.
What ‘double mutant’ means
Officially named B.1.617, the ‘double mutant’ is a bit of a misnomer, because it actually carries 13 mutations, 7 of which are in the spike protein. The nickname comes from two notable mutations found in other variants that appeared together for the first time in this new strain: the L452R and the E484Q mutations.
The L452R mutation in the spike protein was first found in the COVID variant detected in California, which could be up to 20% more transmissible than wild-type strains.
The E484Q mutation seems very similar to the E484K mutations found in the B.1.351 (South African) and P.1 (Brazilian) variants. These are ‘escape mutations’ because it enables these SARS-CoV-2 variants to evade immune protection with monoclonal antibodies, potentially making vaccines less effective. Thus far, current vaccines appear to be holding up against these variants, according to Jetelina.
The exact significance of these mutations is still being worked out.
“Just because there are two worrisome mutations on one variant doesn’t necessarily mean this is [doubly] contagious or [doubly] deadly. The WHO [World Health Organization] has declared B.1.617 a ‘Variant of Interest’ instead of a ‘Variant of Concern,'” she wrote.
The WHO definition of ‘variant of interest’ is one that has been found to cause community transmission, has been found in numerous COVID cases or clusters, or has been found in multiple countries. A ‘variant of concern’ on the other hand is defined as one that has been associated with or has demonstrated increased transmissibility, increased virulence, a change in clinical disease, or decreased effectiveness in treating or controlling the illness.
What is the significance of this variant?
The B.1.617 variant has spread rapidly in India, becoming the dominant strain in the state of Maharashtra in southwestern India. Maharashtra is India’s second most populous state and also home to India’s financial centre in Mumbai.
In December 2020, 271 million people (about one-fifth of India’s population) were already infected with COVID, and modelling studies suggested that natural infection had already caused India to reach herd immunity. In light of this, India’s health minister announced that the country had successfully contained the spread of the virus.
Yet three months later, the biggest COVID surge yet is happening in India, with a new high of over 340 000 new infections reported daily. Furthermore, experts believe the actual number of infections and deaths may be under-estimated.
Is the new variant possibly to blame for the current surge? Or is it a combination of factors related to people letting their guard down, such as a lack of masking, large gatherings of people mixing and travelling together, and a belief that somehow India was already immune?
No-one has answers to this yet, but a similar situation has already occurred elsewhere in the world.
“We saw the same story in Brazil. The city of [Manaus] had over 70% of people ‘naturally’ infected. But, once P.1. hit, they had a major surge,” Jetelina wrote. “Populations that have high ‘natural’ immunity are getting re-infected. It doesn’t look like natural infection will protect us for long. Get your vaccine.”
The variant has been found in the US and 18 other countries and on all continents, except Africa. Preliminary evidence so far suggests that the Covaxin vaccine, an inactivated virus vaccine made in India, is still protective against the double mutant variant. The trial attracted controversy since it was approved in January without a final phase III clinical trial. Scientists in India have also reported that Covishield, which is a viral vector vaccine like AstraZeneca’s jab, has efficacy against the mutant.
Dr Jetelina nevertheless urged vigilance: “The more this virus jumps from person-to-person (regardless of where it’s at in the globe), the more chances it has to mutate,” she wrote. “The more it mutates, the more chances it has to outsmart our vaccines.”
Researchers have found evidence suggesting that the P.1 COVID variant could be twice as transmissible as prior strains. The findings were published in the Journal Science.
The P.1 SARS-CoV-2 variant was first detected in four travellers from Brazil during a routine screening at Haneda airport, Tokyo. Manaus, the capital of the state of Amazonas in Brazil was the origin of the variant. According to preliminary investigations, the virus emerged late in 2020, beginning to spread in November and then quickly became the dominant strain. This prompted many to believe that it could reinfect those infected with the initial strain.
Some 70% of the residents in the city were believed to have been infected during the initial infection period. After variant infections rose in Manaus, the P.1 variant soon spread throughout Brazil, and then to other countries—thus far, it has been detected in at least 37 countries.
The researchers used molecular clock analysis to determine that the virus had 17 identifiable mutations and that three spike protein mutations (N501Y, E484K and K417T) allowed the virus to bind more effectively to host cells. These also may help in evading antibodies, and the researchers also found that P.1 can evade immunity granted by prior strains.
In simulations, P.1 was 1.7 to 2.4 times more transmissible than the prior virus baseline, but whether this was due to longer persistence in the body or increased viral load could not be determined. Additionally, it could not be established if it increased disease severity or raised mortality rates. Though people inffected with the variant were 1.2 to 1.9 times as likely to die, this could have been a result of the severe strain the overburdened healthcare systems were experiencing in the city.
More work is needed to find out whether the P.1 strain can infect those infected with prior strains or have been vaccinated, the researchers said.
Journal information: Nuno R. Faria et al. Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil, Science (2021). DOI: 10.1126/science.abh2644
A study on COVID variants using in vitro tests, available on the preprint server medRXiv, has shown that the South African variant escapes the Sputnik V vaccine.
This study is the first of its kind to show Sputnik V vaccine recipients had reduced neutralising capacity against the B.1.351 and E484K mutant spikes.
When it comes to vaccine design, the most effective vaccines use a stabilised form of the spike protein, while others use the wildtype spike, protecting against severe disease but not infection because of lower levels of neutralising antibodies. A number of SARS-CoV-2 variants of concern (VOC) have mutations on the spike protein, or the E484K mutation, which allows it to escape vaccines and prior immunity.
In South Africa, where 93% of infections are due to B.1.351, the AstraZeneca vaccine, based on the wild-type spike, failed to prevent mild-to-moderate COVID. The Sputnik V or Gam-COVID-Vac vaccine is also based on the wild-type spike. Interim Phase 3 trial results reported an efficacy of 92%, but this excludes current variants and any lineage containing E484K. The current study examined serum neutralisation activity in samples obtained from 12 recipients of the Sputnik V vaccine in Argentina. This country has already detected many independent variants with E484K, with or without N501Y substitutions.
The researchers found that pseudoviruses bearing either the wildtype D614G spike, and the B.1.1.1.7 spike were effectively neutralised by the vaccine sera, in live virus plaque reduction neutralisation assays. The geometric mean titer of neutralising titers was 49, similar to that of the phase III trial.
However, these sera showed moderate to a marked reduction in neutralisation titers against spike protein bearing E484K, and the UK variant. Even at the highest serum concentration used, 9 of the 12 serum samples could not inhibit 50% of B.1351 viral particles, and only half the sera did so against the E484K mutant.
The researchers concluded that, relative to the wildtype spike virus neutralising titers, were reduced by seven-fold against the B.1.351 lineage and three-fold against the E484K spike. They also found that the VOCs with the different spikes showed different modes of escape from antibody-mediated neutralisation by sera elicited by the Sputnik V vaccine. This means that resistance to neutralisation offered by the South African variant occurs by a different mechanism than that of the E484K mutant.
The UK VOC has low resistance to pre-existing or vaccine-induced antibodies, but the B.1.351 variant shows marked resistance. In fact, 8 of 12 samples were unable to reach IC90 at the highest possible serum concentration.
One neutralised the UK variant but none of the other three variants. These findings are of particular concern because all three VOCs carry the N501Y RBD substitution that confers increased affinity for the ACE2 receptor.
This resistance is competitive and is not present at higher serum concentrations. However, this is not true for the mutations in the B.1.351 variant, which escapes neutralisation with undiluted serum.
Though the Sputnik V vaccine likely protects against severe COVID from VOCs, it is troubling that B1.351, as well as all E484K-bearing mutants, is resistant to neutralisation by sera elicited by this vaccine.
However, antibody functions may be different in vivo, and this study does not cover cell-mediated immunity to multiple antigen sites. “Taken together, our data argue that surveillance of the neutralizing activity elicited by vaccine sera will be necessary on an ongoing basis,” the authors wrote.
The knowledge of which variants can still spread among vaccinated and naturally immune individuals will help decide how to contain them with vaccine upgrades.
Preprint information: Ikegame, S. et al. (2021). Qualitatively distinct modes of Sputnik V vaccine-neutralization escape by SARS-CoV-2 Spike variants. medRxiv preprint. doi: https://doi.org/10.1101/2021.03.31.21254660. https://www.medrxiv.org/content/10.1101/2021.03.31.21254660v2
A study of SARS-CoV-2 genomes and epidemic case data has shown that COVID outbreaks emerge with new variants.
“As variants emerge, you’re going to get new outbreaks,” said Bart Weimer, professor of population health and reproduction at the UC Davis School of Veterinary Medicine. The study combined classical epidemiology with genomics, providing a tool for public health authorities to predict the course of pandemics.
SARS-CoV-2 only has 15 genes, but is mutating constantly. The majority of these changes have little impact, but occasionally they result in the virus becoming more or less transmissible.
Together with graduate student DJ Darwin R Bandoy, Prof Weimer at first analysed the genomes of 150 SARS-CoV-2 strains, mostly from outbreaks in Asia prior to March 1, 2020, along with epidemiology and transmission information on those outbreaks.
The classified outbreaks by stage: index (no outbreak), takeoff, exponential growth and decline. Virus transmissibility is set by the value R, or reproductive number, where R is the average number of new infections caused by each infected person.
They combined all this information into a metric called GENI, for pathogen genome identity. Comparing GENI scores with epidemic phases showed that an increase in genetic variation immediately preceded exponential growth in cases, for example in South Korea in late February. In Singapore, however, bursts of variation were associated with smaller outbreaks that were quickly brought under control.
Prof Weimer and Bandoy then looked at 20 000 sequences of SARS-CoV-2 viruses collected over February to April 2020 in the United Kingdom, and compared them with COVID cases data.
They found that the GENI variation score rose steadily with the number of cases. When a national lockdown was imposed in late March, the number of new cases stabilised but the GENI score continued to rise. This shows that control measures such as banning gatherings, mask mandates and social distancing are effective in controlling spread of disease in the face of rapid virus evolution.
It could also help explain “superspreader” events when large numbers of infections result from relaxed precautions at an event.
Prof Weimer said he hopes that health authorities will adopt this method of measuring virus variation and linking it to the local transmission rate, R.
“In this way you can get a very early warning of when a new outbreak is coming,” he said. “Here’s a recipe for how to go about it.”
Researchers at Boston Children’s Hospital have analysed the structure of the SARS-CoV-2 variants, and have found that a tougher spike protein is likely responsible for their greater transmissibility.
Using a cryo electron microscope, the researchers imaged the spike protein down to the atomic level and discovered that the D614G mutation (a substitution of in a single amino acid ‘letter’ in the spike protein’s genetic code) produced a sturdier spike protein.
In the original, wild-type SARS-CoV-2, the spike protein would latch onto a cell’s ACE2 receptor and then fold in on itself, allowing the virus’ outer membrane to more easily fuse with the cell’s surface. However, they were susceptible to folding early, rendering those spike proteins useless. Around half of a SARS-CoV-2’s spike proteins would be folded in this way. However, this also made the virus harder for the immune system to lock on to.
“Because the original spike protein would dissociate, it was not good enough to induce a strong neutralising antibody response,” said research leader Bing Chen, PhD at Boston Children’s Hospital.
When Chen and colleagues imaged the mutated spike protein, fewer are folded early because the D614G mutation blocks the shape change. While the spike protein is sturdier, it comes at the cost of being able to attach less easily to the ACE2 receptor.
“Say the original virus has 100 spikes,” Dr Chen explained. “Because of the shape instability, you may have just 50 percent of them functional. In the G614 variants, you may have 90 percent that are functional, so even though they don’t bind as well, the chances are greater that you will have infection.”
Dr Chen proposed that vaccines currently being updated should be modified for this new spike protein mutation, which should also have the side benefit of making the vaccines more effective.
Applying structural biology to the spike protein, the team had come up with a ‘decoy’ molecule that bound to the spike protein 200 times more strongly than to the body’s ACE2 receptors. This was shown to inhibit the virus in the culture, opening up the door to a new type of treatment.
Journal information: Jun Zhang et al. Structural impact on SARS-CoV-2 spike protein by D614G substitution, Science (2021). DOI: 10.1126/science.abf2303
In a phase Ib/II trial, the AstraZeneca vaccine was ineffective against both the South African SARS-CoV-2 variant or the wild-type virus.
In this South African trial, the vaccine’s overall efficacy versus mild-to-moderate COVID was 21.9% and efficacy against the B.1.351 variant was 10.4%.
Participants’ median age was 30, about 56% were men, and 71% were black. Almost 20% of participants were obese, 42% were smokers, and about 3% of those had underlying hypertension or chronic respiratory conditions. All were HIV negative. The median time between doses was 28 days.
Overall, 19 of 750 in the vaccine group (2.5%) and 23 of 717 in the placebo group (3.2%) developed mild-to-moderate COVID.
In regard to the secondary outcome of testing effectiveness against the B.1.351 variant, the authors note that “the trial was powered for the primary objective of a vaccine efficacy of at least 60% in preventing COVID-19 of any severity, regardless of variants.”
Exploratory analyses found about 33.5% efficacy against COVID of any severity more than 14 days after the first dose. No cases of severe COVID were reported among the participants, but with the groups’ demographics, especially their relatively young age, it was unlikely that severe COVID would be observed in such a small trial.
Professor Shabir Madhi, Executive Director of the Vaccines and Infectious Diseases Analytics Research Unit at Wits, said in a press release that the AstraZeneca results “threw a curveball” after the initial “euphoria” over the effectiveness of the first COVID vaccines. He nevertheless stressed that the AstraZeneca vaccine was still important in preventing hospitals being overrun with COVID patients.
Despite the disappointing results, Prof Madhi said these findings “need to be made in the context of ongoing global spread and community transmission of the B.1.351 variant”.
Journal information: Madhi SA, et al “Efficacy of the ChAdOx1 nCOV-19 Covid-19 vaccine against the B.1.351 variant” N Engl J Med 2021; DOI: 10.1056/NEJM2102214.
The so-called South African variant was identified by an international team of researchers, including biomedical scientists from the University of California, Riverside. They explain the process behind discovering the variants, why they are so concerning, and what the future holds.
“The new COVID variants are the next new frontier,” said Adam Godzik, a professor of biomedical sciences in the UC Riverside School of Medicine. “Of these, the SA and Brazil strains are most worrying. They have mutations that make them resistant to antibodies we generate with existing vaccines. It is commonly believed we are in a tight race: Unless we vaccinate people quickly and squash the pandemic, new variants would dominate to the point that all our COVID vaccines would be ineffective.”
Prof Godzik and Arghavan Alisoltani-Dehkordi, a postdoctoral researcher who joined his lab two years ago, helped characterise the new SA variant by providing its spike protein structure using computer simulations.
Dr Alisoltani-Dehkordi, who was a postdoctoral fellow at the University of Cape Town before she joined UCR, mentioned that research teams at the University of KwaZulu-Natal and UCT discovered the new SARS-CoV-2 variant from samples collected between October 15 and November 25, 2020, in three provinces. By early November, this variant rapidly became the dominant variant in samples from two provinces. The researchers suggested that this may be due to increased transmissibility or immune escape.
“Each SARS-CoV-2 variant has specific mutations defining it,” Dr Alisoltani-Dehkordi said. “Professor Godzik and I used computer modeling to suggest possible structural and functional consequences of spike protein mutations in the SA lineage. Our analysis, confirmed also by several other research groups, shows that some of the mutations potentially result in a higher transmissibility of the virus and a weaker immune response.”
The SA variant has been detected in 40 countries, and is quite likely present in more still.
“This variant is probably spreading in areas where it has not been sequenced and is, therefore, not identifiable,” Prof Godzik said. “In the US, sequencing is still a slow process. In many parts of the country, including Riverside, we have no information whatsoever about variants.”
The SA variant prompted concern among scientists because its mutations allowed it to evade antibody protection, and potentially, vaccines. Indeed, the AstraZeneca vaccine rollout was halted in South Africa due to the low level of protection against this new variant.
“That’s when it received a high level of interest,” Prof Godzik said. “Subsequent research confirmed it is resistant to vaccines and is spreading. South Africa is doing a good job, however, at controlling the variant through quarantining and other measures.”
Common mutational signatures can be seen in each of the newly emerged SARS-CoV-2 variants of concern in the UK, SA, Brazil, and California. But each of these variants also has a unique set of mutations; for example, the SA and Brazil variants have two unique mutations on spike proteins K417N and E484K, respectively. But, as Prof Godzik explains, there is no single “SA variant”, rather a branch on an evolutionary tree. And viruses can acquire mutations and escape at any time.
Prof Godzik thinks COVID will become a permanent feature of our lives. “It takes six months to develop a flu vaccine,” he said. “Models predict the evolution of the flu virus and vaccines are produced before the variants show up. If the predictions are good, the vaccines work. If they miss, a heavy flu season follows. This is how COVID will likely behave. A lot of effort will be invested in predicting what will happen the following year, vaccines would then be updated, and people will need to get a booster shot.”
Amidst a surge of COVID cases and deaths in Brazil that have brought its healthcare system to the brink of collapse, President Jair Bolsonaro has told its citizens to “stop whining”, saying that the country must balance economic concerns against controlling the pandemic.
According to Brazil’s health ministry, the country has suffered 260 000 deaths from the virus, the second highest in the world after the United States.
“Stop whining. How long are you going to keep crying about it?” Mr Bolsonaro said at an event. “How much longer will you stay at home and close everything? No one can stand it anymore. We regret the deaths, again, but we need a solution.”
In order to stave off further disaster, a number of local governments have started taking matters into their own hands by imposing their own curfews and other social distancing measures.
São Paulo’s governor, João Doria, who has been particularly critical of Mr Bolsonaro’s response to the pandemic, called President Bolsonaro “a crazy guy” for attacking “governors and mayors who want to buy vaccines and help the country to end this pandemic”.
“How can we face the problem, seeing people die every day? The health system in Brazil is on the verge of collapse,” Mr Doria said.
This comes as a Duke University scientist, another Bolsonaro critic, warned of the danger of another quarter of a million deaths, and called for an immediate lockdown to help control the situation.
The situation is exacerbated by the emergence of the P.1 variant which emerged in Manaus, and has high transmissibility and the capability to evade immunity, having a 25% to 60% chance of reinfecting an immune individual.
If Brazil continues to let COVID rage unchecked, it risks deadly new variants emerging to threaten the global community, a Duke University neuroscientist in Brazil told The Guardian.
Miguel Nicolelis urged the international community to put pressure on the Brazilian government, which has made little effort to manage its COVID outbreak which has so far left a quarter of a million Brazilians dead. Brazil’s COVID deaths amount to one tenth of the world’s total.
“The world must vehemently speak out over the risks Brazil is posing to the fight against the pandemic,” said Nicolelis who has spent much of the lockdown in his São Paulo flat.
“What’s the point in sorting the pandemic out in Europe or the United States, if Brazil continues to be a breeding ground for this virus?”
He said: “It’s that if you allow the virus to proliferate at the levels it is currently proliferating here, you open the door to the occurrence of new mutations and the appearance of even more lethal variants.”
Manaus, the largest city in the Brazilian Amazon, has already seen the emergence of a deadly, highly transmissible variant, P1, six cases of which have been detected in the UK already. The new variant with its “unique constellation of mutations” may also evade immunity, scientists have warned.
“Brazil is an open-air laboratory for the virus to proliferate and eventually create more lethal mutations,” Nicolelis said. “This is about the world. It’s global.”
The warning comes as hospitals around Brazil are on the verge of collapse, with a record 1726 daily deaths recorded on Tuesday.
“We’ve now gone past 250 000 deaths, and my expectation is that if nothing is done we could have lost 500 000 people here in Brazil by next March. It’s a horrifying and tragic prospect, but at this point it’s perfectly possible,” he said.
Nicoleis puts the blame squarely upon Brazil’s far right President Jair Bolsonaro. “The policies that he is failing to put into practice jeopardise the fight against the pandemic in the entire planet.”
José Gomes Temporão, who was the health minister during the 2009 swine flu pandemic, said Bolsonaro and others would have to be held accountable for their poor response.
“To this day, Brazil doesn’t have a national plan to combat COVID,” Temporão complained, criticising Bolsonaro’s failure to secure sufficient vaccines for Brazil.
“I don’t think there is any other leader who is so obtuse, so backward, who has such a mistaken and warped vision of reality as the president of Brazil,” Temporão said. “History will condemn these people.”
