What is happening in Manaus? In the U.S., mercifully, the pandemic appears to be gradually subsiding, for now — even as Joe Biden warned, in his inauguration speech, that the darkest and deadliest months may still be ahead, the number of newly infected Americans had already fallen dramatically from its late-December peak. And while vaccine administration here has only inched faster since a wave of outrage earlier this month, anxiety has turned to the question of viral evolution — the possibility that, in the form of new strains from the U.K. and South Africa, Brazil and California, the disease might be outracing our efforts to contain it, including those vaccines. The U.K. and South Africa strains have generated both the most coverage and the most research, but the most concerning may be the Brazilian one, also called P.1. In the Amazonian city of Manaus, where antibodies had been previously estimated in 76 percent of the population, there has been a horrifying and deadly dramatic second wave, right in the middle of Brazilian summer in a place believed to have developed a quite robust community immune protection and perhaps true herd immunity. A new “Comment” published Wednesday in the Lancet surveys what we know about the Manaus variant, and offers four possible explanations for what has happened there. None of them are good. Three are quite terrifying.
The first possible explanation is the most optimistic one: Perhaps that 76 percent finding was wrong, and many fewer people in the city had been exposed to the disease than that much-talked-about study suggested. Even before the second wave, there were some indications that the estimate — which was based on mathematical modeling on top of a basic sample set — might have been high: 76 percent would have been above a crudely estimated herd-immunity threshold of 67 percent. But herd-immunity estimates are rarely precise; even when you have the numbers precisely right, there is always a risk of “overshoot,” and nearby Iquitos, in Peru, registered a similar attack rate of 70 percent. As the Lancet authors point out, the true observed seroprevalence in the earlier survey, which was adjusted upward to reflect the dynamics of antibody waning, was 52 percent, and even taking that lower-bound estimate, they argue, should have produced significant-enough community protection to prevent an outbreak like the city’s second wave.
The second possible explanation offered by the authors of the Lancet analysis is that the immunity measured by that earlier survey may already have waned — meaning that at least some significant group of those people estimated to have immunity in October had become vulnerable to infection again. Previous studies have found, to much relief, protection against COVID-19 lasting at least as long as six months after exposure — but because the second wave in Manaus was seven to eight months after the first, it suggests at least the possibility that the shelf life of naturally acquired antibodies could be only six months, with protection dropping fairly rapidly thereafter. Among other things, this would suggest that at least some of those infected in early waves not just in Wuhan, Lombardy, New York, and London may be vulnerable to infection already.
A third possible explanation is that the new variant, like those discovered recently in the U.K., South Africa, and California, is more transmissible than the strains that have dominated the pandemic thus far. (Indeed, this one could have gained an even larger transmission advantage, since the Brazilian variant took over the pandemic in Manaus much faster than the U.K. strain did the British pandemic.) This would mean both that the level of acquired immunity in the population would have to be higher to offer herd immunity protection — perhaps north of 80 percent — and that the disease might be working much more quickly through that relatively small slice of the population. Because of the dynamics of exponential growth, when transmission accelerates like this it also creates many more deaths — indeed many more deaths than by even quite dramatic increases in the lethality of a disease.
The scariest of the possible explanations is even worse — that the new strain isn’t just more transmissible, but that it has achieved a more total “immune escape,” meaning that it could evade antibodies produced by exposure in the first wave and infect again, even those people who’d mounted a robust immune response and would’ve seemed, outwardly, safe. The antibodies hadn’t waned, they had just been made ineffective, in at least a significant number of cases. This is scarier than the possibility of waning transmission, because at least under that theory, antibodies offer protection for a period of time; and it is scarier than enhanced virulence, because it doesn’t just mean that those without antibodies are at heightened risk. Instead, it would mean that existing antibodies could offer little protection, or perhaps no protection at all, with the disease progressing through the community a second time just as quickly and devastatingly as it did the first. In other words, in theory at least, it could mean reducing what appeared to be a well-protected community into a virgin population — and would represent a threat of that kind to any community, anywhere in the world, should the Brazilian variant arrive, as it now has (at least in the form of a single imported case) in Minnesota.
These hypotheses are not mutually exclusive, the authors point out — the new surge could be multiply determined. But whatever is driving it, the picture is scary. A hospital that was overwhelmed in ten days in the spring became overwhelmed, this time, in just 24 hours, the Washington Post reports. Hospital patients arrived at the hospital sicker than in the first wave, “their lungs chewed up with disease.” Local doctors insist the disease is not just more transmissible now but also more severe — and the data show that the epidemic is bigger this time than the first wave.
Over the past few weeks, as anxiety about the new variants has mounted, those hoping to strike a tone of reassurance have pointed to preliminary evidence suggesting that, while existing vaccines may produce a somewhat less robust immune response against the new variants, they did produce what appears to be a sufficient response to them — as one immunologist memorably put it, the vaccines produce “super-awesome” responses to the classic COVID-19 variant and merely “awesome” responses to the new strains. These dynamics are not binary, in other words, with vaccines falling into either an “effective” or an “ineffective” bucket. But while vaccines are still useful with somewhat diminished immune response, across populations the effect can be quite profound — if efficacy falls to, say, 75 percent when herd immunity requires that 80 percent of the population demonstrate protection, then you simply can’t achieve population-scale protection through vaccination alone. There is no research yet into the efficacy of any of the vaccines against the especially concerning Brazilian variant, but, already in Israel, the world’s most effectively vaccinated country, officials are worrying over stubbornly persistent infection rates — suggesting that while their vaccines do offer at least some protection against the British variant particularly, it may not be enough to quickly control the pandemic, even with their gold-standard vaccine deployment rates. In the just-released clinical data for Johnson & Johnson’s much-anticipated single-dose vaccine, which included eye-opening protection against severe disease, hospitalization, and death, efficacy against transmission was 72 percent in the United States, primarily against the classic strain, but dropped to just 57 percent in South Africa, where the new local variant was dominant.
Pull back and the picture grows more concerning — and indeed reveals our focus on vaccine efficacy as a bit of global North narcissism. A forecast published this week by the Economist Intelligence Unit suggested that most of the world’s poor countries are unlikely to reach mass immunization through vaccination before 2024 at the earliest, and may never get there. If the Manaus experience is explained by waning antibodies, that could mean that nations in the developing world would pass through six or eight full pandemic cycles before vaccines arrive at scale. If it is explained by immune escape, the path forward would not necessarily be quite so brutal — it would mean that this variant evolved to evade previous antibody protection, and would tragically reset the clock on all naturally acquired immunity wherever it traveled, but in the absence of new strains adapted to evade antibodies to this one, populations would have to start from scratch, but could build up natural immunity over time. Of course there will almost certainly be more variants coming over those next three years as well.
