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Meet your B cells and T cells, your enduring pandemic protectors

The world is full of so many things that can make us sick — viruses, bacteria, parasites, fungi, even mutated versions of our own cells. The threats are varied and unrelenting, but so too is our immune system. It’s an orchestra of cells, proteins, organs, and pathways that all harmonize to keep invaders at bay. In simplified form, here’s how.

When a pathogen like the coronavirus enters the body for the first time, it confronts the innate immune system, which provides generalized protection against all pathogens, but isn’t always enough to prevent illness on its own. After an infection takes root, the immune system launches a more targeted response with what’s known as the adaptive immune system.

Neutralizing antibodies form the pillar of the adaptive immune system. The virus is studded with spike proteins (giving it its namesake corona, meaning crown in Latin), which attach to human cells to begin the infection process. Y-shaped antibodies can attach to the spikes on the virus and prevent it from entering cells, thereby neutralizing the pathogen. The parts of a virus that can trigger an immune response are known as antigens.

Healthcare workers collect nasal swab samples at a drive-thru COVID-19 testing site at Camping World Stadium in Orlando, Florida. Paul Hennessy/SOPA Images/LightRocket via Getty Images
Controlling Covid-19 transmission with measures like testing, masking, and social distancing is an important way to prevent the rise of new variants.

“In general, neutralizing antibodies keep you from getting infected in the first place,” said Lewis Lanier, chair of the microbiology and immunology department at the University of California San Francisco.

Neutralizing antibodies are picky about the parts of the virus they recognize, known as epitopes. If those attachment points on the virus change, as they do in many coronavirus variants, antibodies can become less effective. In the months following an infection or immunization, the amount of these neutralizing antibodies declines as well. That’s expected. Making antibodies takes a lot of energy, so the body makes fewer of them after an infection is gone.

That decline may sound worrisome, but the immune system has other powerful tools in its shed. To start, there are non-neutralizing antibodies. These don’t directly interfere with how the virus functions, but they can help the immune system detect infected cells and mark them for destruction. This is a crucial task because viruses can’t make copies of themselves on their own: They need to commandeer a host cell to reproduce. Once a virus enters a cell, it’s not accessible to neutralizing antibodies, but non-neutralizing antibodies that learned to recognize infected cells can still raise the alarm.

The task of eliminating infected cells falls to a group of white blood cells known as cytotoxic T cells, sometimes called killer T cells. They arise from stem cells in bone marrow and cause infected cells to self-destruct, without messing with normal cells.

“T cells, they cannot prevent infection,” said Lanier. “The only way a T cell can recognize you have an infection is after a cell has been infected.”

Helper T cells are another important white blood cell variety. They spur the production of antibodies by a different group of white blood cells called B cells. B cells form in bone marrow and then migrate to lymph nodes or the spleen.

After an infection or a vaccination, some B cells and T cells stick around, becoming memory B cells and T cells. They sit idle, sometimes for decades, waiting to see if a pathogen returns. If it does, they can quickly reactivate.

Colored scanning electron micrograph (SEM) of resting T lymphocytes from a human blood sample. Greg Towers, University College London via Getty Images
T cells dispose of infected cells. They also help B cells mature in order to manufacture antibodies.

This is why we a decline in neutralizing antibody counts isn’t always a disaster. Even if concentrations of neutralizing antibodies dip so low that they can no longer prevent an infection, other parts of the immune system can spool up to make sure the virus doesn’t do too much damage.

“There is a window of time after virus gets into the body before it really starts manifesting disease in the person,” said Deborah Fuller, a professor of microbiology at the University of Washington School of Medicine. “That window of time enables the immune system that has been vaccinated and has memory immune responses to recall very quickly and shut down the virus before it actually causes disease.”

Our immune systems are adapting — but so is the virus

Some health officials now say that Covid-19 is so rampant that most people are likely to become infected at some point. “It’s hard to process what’s actually happening right now, which is most people are going to get Covid,” Janet Woodcock, acting commissioner of the Food and Drug Administration told the Senate health committee on Tuesday. “What we need to do is make sure the hospitals can still function, transportation, other essential services are not disrupted while this happens.”

However, waves of infection can crest just as quickly as they form. Countries like the United Kingdom and South Africa experienced awful omicron spikes but subsequently saw precipitous drops in cases thereafter. Omicron cases also appear to be leveling off in some parts of the US, a sign that a decline may be ahead.

Whether these spikes in Covid-19 cases lead to severe health outcomes hinges on the teamwork of B cells, T cells, and antibodies, and how they hold up against any new mutations in the virus. It’s an area of active research for scientists.

“Vaccines and prior infection may not prevent you from being infected by the next waves of variants, but it may well keep you out of the hospital,” Lanier said.

For the past two years, with recurring spikes in Covid-19 cases, neutralizing antibodies have taken center stage. “We’re really more concerned right now in the middle of the pandemic about the durability of that antibody because what we’re trying to do is prevent transmission,” said Fuller. But that could change.

Neutralizing antibodies remain a key benchmark for vaccines: Scientists judge the success and timing of vaccines in part by measuring the number of antibodies they provoke in our blood, and how long the antibodies stick around. When the mRNA vaccines from Moderna and Pfizer/BioNTech were in development, they demonstrated that they could elicit a high level of neutralizing antibodies. Further clinical trials showed that this translated to more than 90 percent efficacy in preventing illness.

The next test is how well antibody production ramps back up if the same virus invades again. It can take up to two weeks to generate antibodies after being exposed to a virus for the first time, but production can ramp up much faster during a second infection.

Illustration of B cells secreting antibodies. Getty Images/Science Photo Library
B cells secrete antibodies that can halt a virus. Some B cells turn into memory cells that store the instructions for making antibodies to a particular pathogen.

At the same time, a virus is rarely the same when it comes back. Viruses mutate frequently as they reproduce, and RNA viruses like SARS-CoV-2 are especially prone to change. Versions of the virus with distinct groupings of mutations are categorized as variants, like omicron, delta, and alpha. Our immune systems are getting stronger and faster, but changes to the virus still have the potential to throw them for a loop.

Already, some companies are developing omicron-specific vaccines, but they may not hit the market for months. The reformulated shots may be too little, too late. In the meantime, we have to rely on the immunity we already have, including boosts to our antibody counts that come from booster doses of Covid-19 vaccines.

We will eventually reach a balance with Covid-19

There is still much to learn about how all the elements of the immune system work together over time to hold off Covid-19, and some of the answers will only become evident with time. And the odd behavior of omicron is forcing researchers to rethink what they’ve learned.

The good news is that many aspects of our immune system also appear to handle the latest variant well. “From what I’ve seen, the T cell responses are still working rather well against omicron,” said Brianne Barker, a vaccine researcher at Drew University. “I think that we’ve still got a bit of time” in which immune protections will remain intact.

Immunity will continue building across the population and will blunt the sharp edges of the pandemic, even as the virus changes. Covid-19 is unlikely to go away entirely. As it circulates, it will continue to mutate and may cause sporadic outbreaks. But our immune systems are making progress.

Transmission electron micrograph of a SARS-CoV-2 virus particle (UK B.1.1.7 variant), isolated from a patient sample and cultivated in cell culture. NIH/NIAID via Getty Images

The SARS-CoV-2 virus, as seen under an electron microscope, with the crown of spike proteins depicted in red.

“As you expose the human body, even to the same antigen over and over again, our immune system evolves as well,” Fuller said. “What we’re starting to see in people with third immunizations is an antibody [response] that is broader.”

It’s a good sign that improvements in our immune system are likely to outpace changes in the virus. But the pandemic has also made it clear that there is nothing about its trajectory we can take for granted. While the cells within us may shield against infection, it’s still a good idea to limit transmission of the virus in any other way we can. The fewer people it infects, the fewer unpleasant surprises ahead.

And we aren’t doing much to prevent it.

Starting in 2014, the impoverished city of Flint, Michigan, experienced the highest-profile lead exposure crisis in recent American history.

Lead levels in Flint’s children spiked after the city failed to properly treat a new water source. Eventually, the state of Michigan and city of Flint were forced to agree to a $641 million settlement for residents affected by the lead poisoning, and several state officials, including former Gov.  Rick Snyder, were criminally indicted for their role in exposing children to lead.

While estimates differ, a prominent study found that the share of screened Flint children under the age of 5 with high lead levels reached 4.9 percent in 2015, up from 2.4 percent before the problems with lead contamination began. According to the CDC guidance at the time, a level of lead in blood that would be considered high was 5 micrograms per deciliter (µg/dL) (the agency has since lowered the threshold to 3.5 µg/dL). That said, no level of lead exposure is considered safe, and even exposure well below public health recommendations can be quite harmful. That nearly 5 percent of young children in Flint faced exposure to rates that high is a travesty.

As scandalous as the Flint lead crisis is, it’s sobering to know that it may be just the tip of the iceberg globally.

A recent systematic evidence review, widely cited and respected in the field, pooled lead screenings from 34 countries representing two-thirds of the world’s population. The study estimated that 48.5 percent of children in the countries surveyed have blood lead levels above 5 µg/dL.

Let me repeat that: Flint became the symbol of catastrophic lead exposure in the United States. The breakdown of a long-neglected system was so terrible that it led to headlines for months and even became an issue in the 2016 presidential election. Yet children in low- and middle-income countries are, per this estimate, 10 times likelier to have high blood lead levels than children in Flint were at the height of the city’s crisis.

The lead problem is global. It’s catastrophic in scope and hurting children’s ability to learn, earn a living when they grow up, and function in society. Yet lead has gotten comparatively little attention in the global public health space. Charities globally are spending a total of just $6 million to $10 million a year trying to fight it. For comparison, individuals, foundations, and corporations in the United States alone spent $471 billion on charity in 2020.

Childhood lead poisoning is a tragedy — and it is one that would be relatively inexpensive for the world to fix.

What lead does to humans

Lead is soft, plentiful, and easy to mine and manipulate, which is why humans have been harnessing it for various purposes for thousands of years. Ancient Romans used lead for everything from water piping to pots and pans to face powder to paint to wine preservatives.

Today, common uses of lead still include cookware, paint, and piping, along with lead acid batteries (a technology still used for most car batteries, even in hybrids), and plane fuel. For decades, a major use of lead was as an additive to gasoline meant to prevent engine knocking. While the US started phasing out leaded gasoline for passenger cars in 1973 — and only finished in 1996 — the last country to officially abandon it, Algeria, did so last year.

The reason we phased it out is that — as we have known at least since Roman times — lead is extremely bad for humans.

Antique shop in Nashville, Tennessee Robert Alexander/Getty Images

A sign on a vintage gasoline pump advises that the gas contains lead (tetraethyl).

“Lead causes toxicity to multiple organs in the human body,” Philip Landrigan, a doctor and professor at Boston College who conducted key studies on the effects of lead in the 1970s, told me. “In infants and children, the brain is the big target. But we also know very well that adults who were exposed to lead — especially people exposed occupationally [and thus exposed to high amounts] — are at very substantially increased risk of heart disease, hypertension, and stroke.”

Lead exposure can be quite deadly. Some of the best evidence here comes from a recent study examining Nascar’s decision to ban leaded gasoline from its cars in 2007. Overall, mortality among elderly people fell by 1.7 percent in counties with Nascar races after the races stopped using leaded gas. The authors estimate that Nascar and other leaded gas races had caused, on average, about 4,000 premature deaths a year in the US.

The biggest costs of lead, though, are its effects on the brains of children. The developing brain is, in Landrigan’s words, “exquisitely sensitive” to the effects of lead. “It damages neurons; the active cells in the brain that we use for reflexing, running, and jumping, everything,” he explains.

The effects of lead “seem to concentrate in the prefrontal cortex,” Bruce Lanphear, a leading medical researcher on lead’s effects based at Canada’s Simon Fraser University, told me. That part of the brain is smaller in adults who were exposed to lead as children, he added. Neuroscientists believe the prefrontal cortex plays a key role in executive functioning: the ability of people to choose behaviors in pursuit of conscious goals rather than acting on impulse. “It’s what distinguishes us from other animals, what makes us human,” Lanphear said.

For just about any variable you can imagine related to human behavior and thinking, there is probably research indicating that lead is harmful to it.

High lead exposure reduces measured intelligence substantially. “If we compare kids at the lower and higher end [of lead exposure], we saw a 5-8 point IQ difference,” Aaron Reuben, a psychologist at Duke University and lead author on a study looking at a cohort in New Zealand, told me. Higher lead levels are associated with higher rates of ADHD and negative changes in personality.

Reuben says his research has found that kids exposed to lead are “less conscientious, less organized, less meticulous. They’re a little less agreeable; they don’t get along as well with others. They’re more neurotic, meaning they have a higher propensity to feel negative emotions.”

In recent years, some writers have embraced a theory that declining lead exposure (mostly due to the gradual removal of lead from gasoline) was a leading factor in the drastic decline in crime, especially violent crime, in the United States in the 1990s. Whether or not lead explains that specific historical phenomenon, several high-quality studies have found a relationship between high lead exposure and crime and delinquency.

One found that Rhode Island schoolchildren exposed to lead were dramatically likelier to be sent to detention. Another, looking at the introduction of lead pipes in the late 19th century, found that cities with the pipes had considerably higher homicide rates. A third, looking at reductions in lead in gasoline in the late ’70s and early ’80s, found that the phase-out led to a 56 percent decline in violent crime.

This evidence is suggestive, not definitive. A recent meta- analysis argued that when you take into account the likelihood of publication bias (that is, that studies showing a strong effect of lead on crime are likelier to be published than studies finding little effect), the effect size could be quite small and not explain any of the decline in homicide rates in the US.

But the idea that lead has a high social cost does not hinge on a specific narrative about crime. Lead appears to be consistently costly across outcomes from IQ to personality to impulse control to elderly mortality.

“Lead has been really bad and very significant in the history of social behavior,” Jessica Wolpaw Reyes, an economist at Amherst College and author of that last paper, summed it up to me.

Lead exposure is still very common in the developing world

The story of lead exposure in the United States and other rich countries in recent decades has in fact been enormously positive. Yes, there have been disastrous lapses as in Flint, but they stand out precisely because they are such an exception to recent trends.

Federal State Of Emergency Declared In Flint, Michigan Over Contaminated Water Supply Brett Carlsen/Getty Images

The City of Flint Water Plant is illuminated by moonlight on January 23, 2016, in Flint, Michigan.

A recent paper from CDC researchers estimated that from 1976 to 1980, fully 99.8 percent of American children aged 1 to 5 had levels of lead in their blood of over 5 micrograms per deciliter. From 2011 to 2016, the share was down to 1.3 percent. In a major triumph for environmental public health, high-level lead exposure went from the norm to an aberration in just four decades, in large part due to the abandonment of lead in gasoline.

As bad as things are in developing countries today, lead exposure in those nations is much less prevalent than it was in the US 40 years ago — a sign of global progress. That said, lead exposure in developing countries appears to be quite high compared to exposure in rich countries today.

Several experts I spoke to pointed to the 2021 evidence review led by Bret Ericson that I referenced above as the best summary of what we know about how common lead exposure is in low- and middle-income countries. In 34 nations, which together account for over two- thirds of the world’s population, the researchers were able to find blood lead surveys they considered reasonably representative of the country’s children, usually conducted by nonprofits or government agencies.

Overall, those studies estimated that 48.5 percent of children had high lead levels (defined as above 5 ug/dL). Levels of exposure varied greatly, with surveys in a few countries (like Tanzania and Colombia) not finding any children with blood lead levels above 5 ug/dL, and other countries showing huge majorities with levels that high. In Pakistan, for instance, over 70 percent of children had high blood lead levels.

Lead levels this high imply incredible amounts of damage to health and well-being. The Global Burden of Disease study published in the Lancet in 2019 estimated that about 900,000 people die due to lead annually, representing 21.7 million years of healthy life lost. One attempt to quantify the economic costs of lead in low- and middle-income countries estimated that in 2011, the burden was around $977 billion annually, or 1.2 percent of global GDP.

Lead in poor countries comes from everything from batteries to turmeric

While the numbers above give a sense of the lead problem’s scale, they are not definitive. One consistent message I heard from experts is that we simply need a lot more data on lead in low- and middle-income countries.

The Ericson evidence review concluded, “there is a paucity of rigorous data on lead exposure in the general populations of [low- and middle-income countries].” Most countries in Africa, and several in Latin America and Central Asia, did not have data usable for the review.

Lead experts also disagree about what the primary sources of lead exposure in developing countries might be. Pure Earth, the largest nonprofit working on lead contamination in developing countries, has generally focused on reducing exposure from informal recycling of lead-acid car batteries. In many developing countries, such recycling happens in mom-and-pop operations in backyards, with no protection for the recycling workers or neighboring residents from the resulting fumes.

But more recently, Pure Earth has also been working on reducing exposure from cookware and spices. Stanford researchers Jenna Forsyth and Stephen Luby have found that turmeric spice in Bangladesh is very often cut with lead chromate. That’s right: The turmeric that Bangladeshis use for cooking often has lead added to it. Lead is very heavy, and in lead chromate form, it’s a vibrant yellow, which makes it an easy way to adulterate and amplify the color of turmeric. The problem likely spans beyond just Bangladesh. Consumer Reports has found that even in the US, grocery stores were selling turmeric cut with heavy metals.

Environmental scientists have worried for years about lead exposure from ceramics in Central America, where traditional processes often use lead for glazing. But Pure Earth’s Richard Fuller told me that ceramics in India often contain lead too, and in many low- income countries, aluminum cookware is contaminated as well. Aluminum pots and pans in these contexts “are generally made in local recycling places where the recyclers are throwing all this scrap metal in,” he said. “It’s almost impossible for them to not get lead in.” In turn, that lead can seep into food cooked using these tools.

But other, smaller organizations focus on different lead sources. Lead Exposure Elimination Project (LEEP), founded in 2020, has mostly focused to date on lead paint. Just as lead can make turmeric more vibrant, it can make yellows and whites in paint more vibrant too. “We decided to start with lead paint because it seemed like a significant source of exposure, and there’s an obvious approach to tackling it, which is regulation,” Lucia Coulter, a medical doctor and LEEP’s co-founder, told me.

Tackling lead paint requires introducing new laws and enforcing old ones. Jerry Toe, an official at Liberia’s Environmental Protection Agency (EPA) who has worked with LEEP on lead paint, told me that while the country had adopted a law banning lead paint in 2004, the Liberian EPA had still not formalized any regulations deriving from it by 2019, when he came to the issue. It took a LEEP study in Malawi for regulators in that country to conduct regular monitoring of lead levels in paints for sale.

Imran Khalid, a researcher at Pakistan’s Sustainable Development Policy Institute and director at the World Wildlife Fund Pakistan, has had a similar experience. “The implementation [of lead regulations] is quite poor,” he told me. “Our environmental laws are primarily lip service.”

Khalid has been working with LEEP on paint sampling studies in which he and other researchers obtain paint from stores and test it for lead. Zafar Fatmi, a professor at Aga Khan University in Karachi, said that in his initial testing, around 40 percent of paints had high levels of lead.

Khalid notes that some high-lead paint comes from major multinationals, which makes enforcement a challenge. “For a country like Pakistan that’s already going to the IMF [International Monetary Fund] again and again” asking for loans, he explains, “people become very hesitant [about criticizing multinationals] when environmental issues come up.”

And there are other possible sources in poor nations as well, including some of the same ones still plaguing rich countries. “A lot of homes in African countries still have lead pipes, and nobody is talking about getting rid of them or what problems they’re creating,” Jerome Nriagu, a professor of environmental health sciences at the University of Michigan and one of the first US researchers to raise alarms about lead in Africa, told me.

An urgent need for more funding and more data

Last year, the effective altruist research group Rethink Priorities released a comprehensive report attempting to assess how many groups were working on lead exposure in poor countries and how much more could be done on the issue. Their answers: Not many are working on this, and those that are could likely use millions of dollars more every year to spend on effective projects.

Pure Earth, formerly known as the Blacksmith Institute, is by far the largest player, but it spends just $4 million to $5 million a year on lead. “Summing estimated budgets of other organizations, we believe that donors spend no more than $10 million annually on lead exposure,” Rethink Priorities’ Jason Schukraft and David Rhys Bernard conclude.

Much of that funding comes from government sources like the US Agency for International Development and the Swedish equivalent Sida. Outside support for nonprofits, there’s not much public evidence that international aid agencies are investing in lead abatement. With some notable exceptions, like the Center for Global Development, groups working on global health have largely ignored the issue.

A group of children wearing shirts that read “For a lead safe future” hold up a large ball that reads “Lead safe paints for our children’s health, Eco Waste Coalition.” Jay Directo/AFP via Getty Images

Children advocate for the removal of lead in paint at a public school in suburban Manila, Philippines, on June 4, 2015, which was World Environment Day.

Ten million dollars a year, tops, is not much money at all to spend fighting global lead poisoning, even with increased investments directed by donors in the effective altruism community toward Pure Earth and LEEP. “It’s a fairly small community, and it’s remarkably small given the scale of the problem and the scale of the impacts,” Pure Earth’s Fuller said. That helps explain why effective altruist groups like Rethink Priorities and GiveWell have become interested in lead alleviation. It’s a neglected area, where each additional dollar can go a long way.

So what else could be done with more money and resources? One simple answer is better research. When I asked Fuller and his colleague Drew McCartor what additional studies they’d do if they could, they immediately said basic lead exposure surveys in affected countries and basic sourcing analysis to see where lead is coming from in those countries.

We have such poor data on how many people (especially children) are being exposed to lead and on how they’re being exposed to lead, that improving that data could in turn significantly enhance nonprofits’ ability to target interventions effectively. If, say, lead pipes are a bigger source of exposure in sub-Saharan Africa than previously thought, that would change how Pure Earth and other groups allocate funds; likewise, a finding that lead paint is not a significant source of exposure might change LEEP’s approach.

Rethink Priorities concluded that “existing and potential new NGOs in the area currently have the capacity to productively absorb $5 to $10 million annually in additional money,” and that sums above that amount might be productively usable too.

That’s just not a lot of money in the context of US foundations or even foreign aid budgets — especially for something we know is severely injuring children and killing adults in the developing world.

Pedestrians walk past a public awareness sign encouraging social distancing and hand-washing to help reduce the spread of the coronavirus in Tokyo, Japan, on June 22, 2021.

Messages should be simple. The Japanese government’s “three Cs” — urging people to avoid closed spaces, crowded places, and close-contact settings — is seen as one of the more effective messages of the pandemic. This Vietnamese hand-washing PSA went viral in the spring of 2020, driven by a catchy song and a dance.

Suzanne Bakken, who has contributed to the National Academy’s work on Covid communications, told me that “flatten the curve” had been the most effective message deployed in the United States. It managed to communicate an important public health goal in an intelligible fashion and, for a time, gave people a shared goal to work around.

“That really spoke to people,” she said. “It was a pretty simple visualization.”

Academics such as Bakken are also thinking about how to empower local health authorities and nongovernmental groups, in which people might place more trust in the current polarized political environment. The National Academy of Medicine review contemplates some kind of national infrastructure that would disseminate information to local actors and allow them to decide how to tailor the message based on their particular community:

Communications should be adapted at the individual and community levels and take into account how centrally developed communications methods can be rooted in patriarchy, colonial oppression, and structural racism. Without this understanding, communications cannot be appropriately adapted to local contexts, and therefore may be rejected by many communities.

This is a lesson that other countries more accustomed to public health emergencies have already learned. In Vox’s Pandemic Playbook series, reporter Jen Kirby traveled to Senegal and spoke with community health workers who were integral to that country’s response, as the point of contact and primary communicator in their own villages and towns.

Given how diverse the US is, and how much trust in some of its national institutions has eroded, such a model would offer one way to begin repairing the relationship between the American public and its public health institutions.

“It’s not only getting the message right,” Ratzan said, “but having the right messenger, with the right dosage.”

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