New variants of SARS-CoV-2 that potentially escape human immune response have the world on edge, raising concerns as to whether they will undermine efforts to bring the pandemic under control with vaccination.

There are no easy answers, mainly because the data are ambiguous or lacking entirely. Reinfections have been notoriously difficult to get a handle on, as viral genome sequencing isn’t ubiquitous, making it difficult to compare two separate infections in the same person over a period of time. (Plus, reinfections will never be identified as such in people whose initial bout went undetected.) It’s therefore impossible to say definitively whether reinfection is occurring more frequently now with new variants compared to wild-type virus.

Still, the general consensus is that reinfections remain underestimated but rare, and the information that is available, mainly from vaccine trials, generally paints an optimistic picture.

Here we break down the science behind the two most common “variants of concern:” B.1.351, or the South African variant, and P.1, the Brazilian variant. While there are some reports that B.1.1.7, the so-called U.K. variant, has picked up a mutation that could make it look more like the other two potential escape variants, it is not yet thought to be as problematic as the other two.

South African Variant

Last week, Soumya Swaminathan, MD, chief scientist of the World Health Organization, called attention to preliminary reports from South Africa regarding reinfections with the B.1.351 variant, though she didn’t give specific details.

Swaminathan may have been referencing the 4,000 cases of reinfection under investigation in the country, as mentioned by Koleka Mlisana of South Africa’s National Health Laboratory Service in a mid-January interview.

Mlisana said that, as of Jan. 6, “we really have seen a constant risk of reinfections, which means we have not seen a marked increase … apart from the increased number of infections. We are not necessarily seeing an increase in risk of reinfection.”

“So far we are able to say there is no evidence that suggests the risk of reinfection is increasing as a result of the new variant,” she continued. “But we are only talking about a month so far. This is an area we need to look very closely.”

It’s not clear if further investigation has changed that understanding.

Indeed, on Feb. 7, the country decided to halt the rollout of Oxford/AstraZeneca’s COVID-19 vaccine after an analysis suggested “minimal protection” against mild-to-moderate illness from the variant. However, experts cited a host of cautions about the study, including that it was conducted in a younger and healthier sample, was underpowered, and could not evaluate protection against severe infection.

Nevertheless, the WHO recommends that governments should continue using the AstraZeneca vaccine even if they’ve confirmed the presence of the South African variant in their countries. Yet South Africa has started to give the Johnson & Johnson vaccine to its healthcare workforce, even though the product hasn’t been formally authorized there or anywhere else.

Clinical data from studies of the Johnson & Johnson and Novavax vaccines do show an overall decrease in efficacy against B.1.351, but protection against severe illness appears robust. The J&J product’s efficacy against moderate-to-severe illness was 57% in South Africa versus 72% in the U.S., but showed 85% efficacy at preventing severe disease across all regions 28 days after dosing — and there were no cases of severe illness in vaccinated participants anywhere 49 days after the single-dose shot.

Novavax showed overall efficacy of 49.4% for preventing mild, moderate, and severe illness in its South Africa study, albeit with a very wide confidence interval. That figure rose to 60% when looking only at HIV-negative participants, again with a wide confidence interval.

The Pfizer and Moderna vaccines both showed diminished neutralizing antibody activity against the South African variant, but the companies said these responses were still likely to be protective.

Still, at least one case of severe reinfection with the South African variant has been reported in the literature, in Clinical Infectious Diseases. In September, a 58-year-old male patient in France was confirmed COVID-positive with symptoms of mild fever and shortness of breath that resolved in a few days. But in January, he tested positive again and eventually needed intubation. He was confirmed to have the South African variant on the second illness. Researchers weren’t able to sequence the virus involved in his September infection, but said it was unlikely to be the South African variant because it first emerged in October and wasn’t detected in France until December. On the other hand, the WHO said the South African variant developed as early as August.

Also, Israel has confirmed three cases of reinfection with the South African variant but, as noted earlier, there’s no proof of increased rates versus the wild-type virus.

Brazilian Variant

What’s happening in Manaus, the capital city of Brazil’s Amazonas region, has been of even greater concern to virologists and epidemiologists.

Some work had suggested that the city, which was hit very hard during the first wave of the pandemic in spring 2020, had reached herd immunity. A paper published in Science in mid-January by Ester Sabino, MD, PhD, of the University of Saõ Paulo, and colleagues estimated an infection rate as high as 76%, based on antibody levels in blood donations.

Just a few weeks later, Sabino and colleagues wrote a follow-up paper in The Lancet calling attention to the sharp increase in hospitalizations in Manaus that quickly overwhelmed the healthcare system there. They noted that after the spring peak, hospitalizations remained “stable and fairly low for 7 months from May to November, despite the relaxation of COVID-19 control measures during that period.”

They posed four possible explanations for what happened in Manaus, which aren’t mutually exclusive: the attack rate could have been overestimated during the first wave and herd immunity never achieved; immunity waned; an escape variant emerged that overcame “natural” immunity; and/or the novel variant is more transmissible, raising the threshold for herd immunity.

“The new SARS-CoV-2 lineages may drive a resurgence of cases in the places where they circulate if they have increased transmissibility compared with pre-existing circulating lineages and if they are associated with antigenic escape,” Sabino and colleagues wrote. “For this reason, the genetic, immunological, clinical, and epidemiological characteristics of these SARS-CoV-2 variants need to be quickly investigated.”

Warner Greene, MD, PhD, director of the Gladstone Institute at the University of California San Francisco, told MedPage Today earlier this month that Brazil likely holds the answer to the future of the pandemic.

“I would like to know whether or not there was real herd immunity. Before this new variant, was there clear evidence of good antibody response and retention of good antibody response against the original strain, the wild-type virus?” Greene said. “If in fact there was intact immune response and this variant was able to overwhelm this response, that’s not good news. But if it waned or never developed fully, that’s a less daunting problem.”

Greene noted that, even if variants do manage to evade antibody attack, T cell responses are typically more robust and harder to dodge.

When Will We Know?

If there’s a confirmed jump in reinfections, or if large numbers of vaccinated people start developing the disease, that’s when we’ll know whether escape variants have become a genuine new threat, experts say.

Companies are preparing for the possibility, with both Moderna and Pfizer saying they’re working to update their vaccines. The mRNA platform makes it relatively easy to do so. The FDA has said it’s developing a pathway to speed booster shots to market.

That doesn’t mean people shouldn’t be vaccinated now, experts emphasize, especially as vaccine-induced immunity appears to have an advantage over natural immunity.

“Don’t use the idea that variants are emerging as a reason not to get vaccinated,” said Jasmine Plummer, PhD, of Cedars-Sinai Medical Center in Los Angeles. “It should push us to get vaccinated more quickly.”

“The FDA said it would approve a vaccine that’s 50% effective. Most studies, even with escape variants, are still higher than that,” Plummer told MedPage Today. “We need to get people vaccinated as quickly as possible. Yes, there will be variants that escape, but with more people vaccinated, the greater chance we have of curbing it.”

Plummer and her team recently discovered a new variant in Southern California called CAL.20C, which she expects will behave more like the U.K. variant: while it appears more transmissible, it does not seem to have escape potential at this point, she said.

Better population-level genomic sequencing in the U.S. is needed to get an epidemiologic handle on variants and how well our efforts to curb them are going, she said.

Sequencing is currently handled at individual laboratories in the U.S., without unified coordination, Plummer said: “It would be amazing to have a centralized [repository] going forward.”