Sure enough, the United States is again awash in virus, with the incidence of new COVID-19 cases having soared 131 percent in the third week of July. To be clear, the vaccines available work well—especially the Pfizer and Moderna products based on mRNA technology. But it is likely that waning vaccine efficacy, coupled with a stubborn one-fifth of the adult population refusing any immunization, has opened the door for the dangerous mutant delta variant of SARS-CoV-2 to wreak havoc among the vaccinated and unvaccinated alike.
That’s why the United States is going to need a third dose of mRNA vaccines; for the nation’s older population, the triple play is already overdue. “I don’t see the virus just disappearing,” said Stanley Plotkin, considered the godfather of vaccinology. The University of Pennsylvania vaccine inventor and immunologist told me that the U.S. Food and Drug Administration (FDA) should comply with requests from Pfizer, following Israel’s example, and immediately approve third-dose immunization for adults over the age of 60, with general triple dosing for all Americans to follow. I agree.
The World Health Organization (WHO) has voiced opposition to third dosing in richer nations before making primary doses available to billions of people in middle-income and poorer countries. It’s a completely reasonable point, both morally and strategically, in the war against COVID-19. But evidence now points in an alarming new direction, suggesting that fully vaccinated individuals can carry the delta variant in their noses and mouths, shedding in some cases just as much virus to infect others as do unvaccinated infected individuals.
Moreover, in the absence of fully effective vaccination of better than 75 percent of adults, a society may act as a herd of walking petri dishes, cultivating immune-escape mutant forms of SARS-CoV-2—that is, mutants that evade existing vaccines. The vaccine that rolls out tomorrow in a poorer country may have already been rendered less effective by its prior inadequate, or incorrect, use in richer countries.
Urgent action is required from the FDA, the U.S. Centers for Disease Control and Prevention (CDC), and their counterparts in Europe, Canada, and other parts of the world that have already widely administered vaccines. And recommending the usage of masks, while necessary, is no longer enough. The message must be that if you’ve had a second shot, it’s time to start planning to get a third.
The example of Israel clearly suggests as much. Because it was the first nation to mass vaccinate its population, scientists around the world are paying close heed to events unfolding there. The government began rolling out the first doses in January and by July had achieved two-dose immunization of 58 percent of its population over 12 years old. Though an estimated 1 million adults still refused vaccination, the government eased nearly all behavior-restricting regulations, including mask-wearing.
But by July the Israeli miracle sobered up, revealing that fully vaccinated people were protected against severe disease and death but not necessarily against infection. In early July, the Ministry of Health announced effective immunity among the fully vaccinated had dropped to 64 percent, from the 95 percent level measured two months previously. Then, on July 17, the ministry reported a surge in breakthrough cases involving the delta variant. Most cases occurred in people either who had been fully vaccinated more than four months previously, indicating the waning immunity problem, or who were just completing their shots in July, too recently to be completely effective.
The data from vaccinated Israeli medical staff shows that while breakthrough infections aren’t life-threatening, they are also not benign: 19 percent of cases led to so-called “long-haul COVID-19,” featuring months of difficult symptoms that can include acute fatigue, depression, loss of stamina and muscle strength, brain fog, and other challenging disabilities.
A multinational study of six months’ use of two-dose Pfizer vaccine also found that efficacy wanes with time, from about 97 percent to a low of 86 percent—still robust. But none of the work involved delta variant exposure. A recent study in Scotland showed that both the AstraZeneca and Pfizer vaccines were considerably less able to prevent delta infection, compared with the alpha strain or original 2020 forms of the coronavirus. (No similar data has been published for the nearly identical Moderna vaccine, but most vaccine experts assume that what holds for Pfizer is also true for Moderna.)
The biology behind all this matters and explains the global delta variant surge. Whether an individual is immunized against SARS-CoV-2 via natural infection or vaccination, there are four key elements necessary to guarantee defense against future reinfection and protection from hospitalization or death. The most important is a huge antibody response against the spike proteins that protrude from the surface of the SARS-CoV-2 viruses and attach themselves to ACE2 receptors located on the outside of hundreds of types of human (and all mammalian) cells. The antibodies must be capable of neutralizing the enemy.
The neutralizing antibodies are made in the second key element of defense—B cells, which are white blood cells and lymphocytes found inside bone marrow and in lymph nodes dispersed around the body and in the spleen. Those B cells must retain what immunologists call “memory”—the key to why, for example, a measles shot administered to a 2-year-old protects the same person as a 40-year-old when exposed to the virus. The B cell memory recognizes the measles and triggers manufacture of those fierce neutralizing antibodies.
The third component essential to protecting people against COVID-19 infection and illness is the antibodies that target other parts of the virus, especially the mechanism SARS-CoV-2 uses to poke itself into human cells and invade. And the final necessity is so-called CD8 and CD4 cells from the T cell side of the immune response, which are capable of calling to the battlefield a vast array of virus-eating cells and releasing chemicals that alert defenses in every organ of the body.
Amazingly, the mRNA vaccines and, to a lesser degree, other non-RNA types made by Johnson & Johnson, AstraZeneca, Russia, and Chinese drugmakers all arm this full range of necessary weaponry against SARS-CoV-2. But they do so with widely varying degrees of efficacy—especially as applied to the delta variant.
When the first three variant forms of SARS-CoV-2 were discovered in the United Kingdom, South Africa, and Brazil, respectively, many immunologists and vaccine experts were quick to say the vaccines still worked—just somewhat less well—against them. Concern about the variants was labeled alarmist at the time. One prominent vaccine expert responded in March to my persistent queries about the first wave of variants by writing that I was “obsessed by the variants to a deeply unhealthy extent that can badly influence public confidence.”
The lion’s share of variant studies executed worldwide in the spring pivoted on the question of how well the vaccines stood up to the mutants. The studies generally concluded that neutralizing antibodies were less abundant in reaction to, say, alpha exposure but remained sufficient to stave off disease, if not infection. Deep sighs of relief were exhaled, albeit with the warning that it remained dangerous to have large percentages of societies unable, or unwilling, to obtain vaccination, as there might arise in the future from that unprotected population a worse mutant form of SARS-CoV-2.
And so it passed in mid-March that the mutant delta variant spread across India like a wildfire, the country recording 400,000 deaths officially by July—a toll widely believed to represent a tenfold undercount. Nearly every country in the world is now battling the delta variant, which threatens athletes in the Tokyo Olympic Village, has spawned a new outbreak in China, and is pushing Africa’s worst COVID-19 epidemic to date.
The delta variant has numerous mutations that give it special attributes. The spike protein that is vital to viral attachment to cells is altered so that it’s harder for the immune system to see it and generate slews of neutralizing antibodies—a case of immune-escape mutation. The proteins it uses to get inside human cells are also mutated so that they dodge the immune system and function efficiently. And the virus is able to generate copies of itself far more rapidly and efficiently. Within three to five days, the viral load of delta peaks at levels up to 1,000 times higher than seen with 2020 forms of SARS-CoV-2.
The implications in the real world of these biological findings are overwhelming. Because the virus surges so rapidly after infection, peaking its viral load two or three days faster than garden-variety COVID-19, individuals who are carrying all that virus in their bodies have no idea, exhibit no symptoms, and take no special precautions to protect others. Worse, even if they were immunized by either vaccines or prior COVID-19 illness, they may be vulnerable to reinfection. That’s for two reasons. First, the sheer volume of virus coming at their unmasked faces from a delta-infected individual is three orders of magnitude larger than anything their bodies were prepared for—instead of encountering a few puffs of particles in the air, they are gulping down microscopic hurricanes of the stuff. And secondly, it surges inside their bodies faster than their B cell memory component can mobilize to generate neutralizing antibodies and other weaponry.
According to Israel, and to Pfizer, vaccine-induced immune response shifts from a powerful form replete with neutralizing antibodies drifting in the bloodstream to the quieter B cell memory type within about four months’ time after the second dose. Neutralizing antibody production declines, Pfizer says, about 6 percent per month, hitting 84 percent vaccine efficacy by month six. By eight months, it’s all about memory, which leaves the individuals highly vulnerable to infection.
In other words, the two-dose vaccinated individuals may have primed immune systems that can make neutralizing antibodies against SARS-CoV-2, but the enemy is coming at them in such massive numbers, and surging inside their bodies so rapidly, that some six to eight months after completing vaccinations, they may be unable to muster adequate defenses to prevent illness, even long-haul COVID-19.
Worse, from a public health point of view, these vaccinated individuals may have billions of virus in their noses and throats, passing them on to others. They can be transmitters. And if the unfortunate recipient is an unvaccinated person, the experience could easily be lethal.
All this is why Israel is starting a third round of national vaccination and why Pfizer wants the CDC and FDA to approve the same for the United States. According to data Pfizer presented to stock shareholders recently, the company estimated that a third booster shot had the potential to increase neutralization of the delta variant by up to a hundredfold, compared with before the third dose.
It also appears that the United States may have blundered by setting the time interval between the first two doses at 21 days—a decision made by the CDC and FDA under the Trump administration. For reasons having less to do with science than with the rush to get as many British at least partially protected as rapidly as possible, Boris Johnson’s government chose a far longer time interval between doses—months. And that may explain why the delta variant’s dire impact seems to be reversing in the U.K., with daily incidence of new cases dropping rapidly. Plotkin, the vaccine inventor, says longer times between jabs—perhaps six months—give the immune system time to settle into its lulled memory status before getting another jolt of fake infection (which, after all, is what a vaccine is), prompting the manufacture of neutralizing antibodies. That length-of-interval issue has arisen with other vaccines, he says, consistently showing months, not days, are required between doses.
Across the richer world, a grand experiment is playing out, as countries try to vaccinate their way out of the pandemic. And, of course, the experiment is being conducted against a mutable, evolving target—a shape-shifter, not an archer’s bull’s-eye. The more people are in circulation, carrying and spreading SARS-CoV-2, the greater the likelihood that the delta variant, or some other form of the virus, will mutate into an even more canny, dangerous human pathogen.
Americans could feel more confident about the national effort to control the virus if they did a far better job of genomic surveillance, scouring the nation for new types of SARS-CoV-2. But despite provision of emergency funds to the CDC for this purpose, the nation’s ability to spot new variants is little improved over what it was back when alpha first showed up in the U.K. last September. Even the CDC’s target of 20,000 samples sequenced and analyzed per week from collection sites all over the United States seems woeful, given some 60,000-80,000 new cases of COVID-19 are identified daily in the country. A super-virulent new variant could lurk in Arkansas right now, and we wouldn’t have any way of spotting it with the meager system now in place. Moreover, the lag time from an individual walking into a clinic for a COVID-19 test to that sample getting sequenced in a separate lab to that lab then reporting its findings to the CDC for analysis is a matter of weeks in many parts of the country and several days even in the best-case scenario. So policymakers are scrambling to change mask rules, vaccine authorizations, school reopening plans—all based on sparse information about last week’s epidemic situation or what it was two weeks ago.
Worse, the basic case numbers—how many people develop COVID-19 symptoms in a given week—are grossly underreported in the United States. It’s possible that as many as 60 percent of cases nationwide are never reported up the public health food chain to be added to the CDC’s national tally. (Most of Europe isn’t doing much better, according to WHO.)
In Atlanta, CDC scientists are scrambling to comprehend what havoc the variant strains are wreaking, how well the vaccines are working, and what forecast ought to end up on the president’s desk. For several months, the CDC has refereed a sort of artificial intelligence conference of modelers and forecasters from all over the United States, mostly academics. Each epidemic modeling team uses its own methodology to track the U.S. epidemic and forecast where it’s headed. Some of the teams are very cautious and consistently lowball the scale of future trends. Some routinely tend to the opposite extreme. The CDC grinds it all up to reach a sort of projection consensus. And so far, these forecasts have been scary correct.
In its latest modeling mashup, the CDC forecast predicts that the new delta-driven surge won’t peak until October, possibly not until Thanksgiving. By late August, at least 2,500 Americans will die, every week, bringing the nation’s cumulative mortality to some 660,000.
With a forecast so grim, it’s time for a Hail Mary move. And that would be the mass third-dose vaccination of every American over 60 years of age, coupled with a return to mask-wearing and social distancing and a massive escalation in genomic surveillance nationwide. Anything less means ceding the battlefield to the virus.
