“We are now engaged in another deadly episode in the historic battle of man versus microbe. These battles have shaped the course of human evolution and of history. We have seen the face of our adversary, in this case a tiny virus.” I spoke these words in testimony before a U.S. Senate subcommittee on September 26, 1985. I was talking about HIV, but I could say the same thing today about the coronavirus we are facing.
Like all viruses, coronaviruses are expert code crackers. SARS-CoV-2 has certainly cracked ours. Think of this virus as an intelligent biological machine continuously running DNA experiments to adapt to the ecological niche it inhabits. This virus has caused a pandemic in large part because it acted on three of our most human vulnerabilities: our biological defenses, our clustering patterns of social behavior and our simmering political divides.
How will the confrontation unfold in the next years and decades? What will be the human toll in deaths, ongoing disease, injuries and other impairments? How effective will new vaccines and treatments be in containing or even eradicating the virus?
No one can say. But several lessons from the long battle with HIV, the human immunodeficiency virus that causes AIDS, suggest what may lie ahead. HIV/AIDS is one of the worst scourges humans have encountered. As a code cracker, HIV is an expert. By the end of 2019 the global death toll from this virus was roughly 33 million people. In all, 76 million people have been infected, and scientists estimate another 1.7 million people acquire the virus every year.
Yet we must appreciate what our scientific defenses have accomplished. Of the nearly 38 million people currently living with HIV/AIDS, 25 million are receiving full antiretroviral treatments that prevent disease and suppress the virus so well they are unlikely to pass it along. I would wager that another 25 million or more infections never happened, primarily in sub-Saharan Africa, because these treatments became available in most countries.
From fighting this epic war against AIDS, doctors, virologists, epidemiologists and public health experts have learned crucial lessons that we can apply to the battle we are currently waging. For instance, we saw that vaccines are never a guarantee but that treatments can be our most important weapon. We discovered that human behavior plays a vital role in any disease-fighting effort and that we cannot overlook human nature. We have also seen how critical it is to build on knowledge and tools gained fighting earlier outbreaks—a strategy only possible if we continue funding research in between pandemics.
Vaccine Challenges
Early observations of how HIV behaves in our bodies showed the road to a vaccine would be long and challenging. As the outbreak unfolded, we began tracking antibody levels and T cells (the white blood cells that wage war against invaders) in those infected. The high levels of both showed that patients were mounting incredibly active immune responses, more forceful than anything we had seen for any other disease. But even working at its highest capacity, the body's immune system was never strong enough to clear out the virus completely.
Unlike the hit-and-run polio virus, which evokes long-term immunity after an infection, HIV is a “catch it and keep it” virus—if you are infected, the pathogen stays in your body until it destroys the immune system, leaving you undefended against even mild infections. Moreover, HIV continually evolves—a shrewd opponent seeking ways to elude our immune responses. Although this does not mean a vaccine is impossible, it certainly meant developing one, especially when the virus hit in the 1980s, would not be easy. “Unfortunately, no one can predict with certainty that an AIDS vaccine can ever be made,” I testified in 1988 to the Presidential Commission on the HIV Epidemic. “That is not to say it is impossible to make such a vaccine, only that we are not certain of success.” More than 30 years later there still is no effective vaccine to prevent HIV infection.
From what we have seen of SARS-CoV-2, it interacts with our immune system in complex ways, resembling polio in some of its behavior and HIV in others. We know from nearly 60 years of observing coronaviruses that a body's immune system can clear them. That seems to be generally the case for SARS-CoV-2 as well. But the cold-causing coronaviruses, just like HIV, also have their tricks. Infection from one of them never seems to confer immunity to reinfection or symptoms by the same strain of virus—that is why the same cold viruses return each season. These coronaviruses are not a hit-and-run virus like polio or a catch-it-and-keep-it virus like HIV. I call them “get it and forget it” viruses—once cleared, your body tends to forget it ever fought this foe. Early studies with SARS-CoV-2 suggest it might behave much like its cousins, raising transient immune protection.
The path to a SARS-CoV-2 vaccine may be filled with obstacles. Whereas some people with COVID-19 make neutralizing antibodies that can clear the virus, not everybody does. Whether a vaccine will stimulate such antibodies in everyone is still unknown. Moreover, we do not know how long those antibodies can protect someone from infection. It may be two or three years before we will have the data to tell us and any confidence in the outcome.
Another challenge is how this virus enters the body: through the nasal mucosal membranes. No COVID-19 vaccine currently in development has shown an ability to prevent infection through the nose. In nonhuman primates, some vaccines can prevent the disease from spreading efficiently to the lungs. But those studies do not tell us much about how the same drug will work in humans; the disease in our species is very different from what it is in monkeys, which do not become noticeably ill.
We learned with HIV that attempts to prevent virus entry altogether do not work well—not for HIV and not for many other viruses, including influenza and even polio. Vaccines act more like fire alarms: rather than preventing fires from breaking out, they call the immune system for help once a fire has ignited.
The hopes of the world rest on a COVID-19 vaccine. It seems likely that scientists will announce a “success” sometime this year, but success is not as simple as it sounds. As I write, officials in Russia have reported approving a COVID-19 vaccine. Will it work? Will it be safe? Will it be long lasting? No one will be able to provide convincing answers to these questions for any forthcoming vaccine soon, perhaps not for at least several years.
We have made remarkable improvements in our molecular biology tools since the 1980s, yet the slowest part of drug development remains human testing. That said, the infrastructure created for HIV/AIDS research is accelerating the testing process now. Thirty thousand volunteers around the world participate in networks built by the National Institutes of Health for studies of new HIV vaccine candidates, and these networks are being tapped for initial testing of COVID-19 vaccines, too.
When doctors treat a patient who is likely to die, they are willing to risk that a drug might sicken the patient but still save their life. But doctors are less willing to do that to prevent disease; the chances of causing greater harm to the patient are too high. This is why for decades the quest for a vaccine to prevent HIV infection has lagged so far behind development of therapeutic drugs for HIV.
Focus on Treatments
These drugs now stand as an incredible success story.
The first set of HIV drugs were nucleic acid inhibitors, known as chain terminator drugs. They inserted an additional “chain terminating” nucleotide as the virus copied its viral RNA into DNA, preventing the HIV chain of DNA from elongating.
By the 1990s we had gotten better at using combinations of drugs to control HIV infections soon after patients were exposed. The first drug, AZT, found immediate application for health care workers who accidentally had a needlestick injury that infected them with contaminated blood. It was also used to reduce mother-to-child transmission. For example, prenatal treatments for mothers with AIDS at that time reduced the number of babies born infected by as much as two thirds. Today combination chemotherapy reduces mother-to-child transmission to undetectable levels.
The next set of drugs was protease inhibitors, one of which I helped to develop. The first was introduced in 1995 and was combined with other drugs in treating patients. These drugs inhibited the viral protease enzyme responsible for longer precursor proteins in the short active components of the virus. But there is a fundamental problem with these drugs, as well as those that inhibit viral polymerases, which help to create virus DNA. Our bodies also use proteases for normal functioning, and we need polymerases to replicate our own nucleic acids. The same drugs that inhibit the viral proteins also inhibit our own cells. The difference between a concentration in which the drug inhibits the virus target and a concentration in which it hurts the human proteins is called the therapeutic index. The therapeutic index gives you the window in which the drug will be effective against the virus without causing undue side effects. That window is rather narrow for all polymerase and protease inhibitors.
The gold standard for AIDS treatment now is called antiretroviral therapy—essentially patients take a cocktail of at least three different drugs that attack the HIV virus in different ways. The strategy is based on earlier success we had in fighting cancer. In the late 1970s I established a laboratory at Harvard University's Dana-Farber Cancer Institute to develop new drugs to treat cancer patients. Cancers developed resistance over time to single drugs, but combinations of drugs were effective in slowing, stopping or killing the cancers. We took that same lesson of combination chemotherapy to HIV. By the early 1990s the first combination AIDS treatments were saving the lives of people infected with HIV. Today an infection is far from the death sentence it used to be—patients can now live almost unaffected by HIV, with a relatively minimal impact on life expectancy.
We already know resistance to single drugs will bedevil COVID-19 treatments. We have seen resistance to single, anti-SARS-CoV-2 drugs develop rapidly in early lab studies. Just as with AIDS and cancer, we need a combination of medicines to treat this disease. The goal of the biotechnology and pharmaceutical industries now is to develop an array of highly potent and specific drugs, each of which targets a different function of the virus. Decades of research on HIV has shown the way and gives us confidence in our eventual success.
Human Behavior
In trying to understand and counter the AIDS epidemic, physician and virologist Robert Redfield (who is now head of the Centers for Disease Control and Prevention) and I became good friends in the early 1980s. We quickly learned that while many politicians across the globe refused to recognize HIV as a threat to their populations, militaries were an exception. Nearly all countries considered AIDS a serious danger to troops and military readiness and a potentially huge drain on future military funds. Their view was, “Let's not blind ourselves and pretend soldiers are saints. They are not. They are humans.” Redfield, then at Walter Reed Army Medical Center, helped to design and manage a program to test the entire U.S. uniformed forces for HIV infection (although the consequences of this test were controversial, and recruits who tested positive were barred from service).
At the time there were no effective drugs; the disease killed more than 90 percent of those infected. When married couples were tested and one partner was infected and one not, doctors advised them in the strongest possible terms to use condoms. I was stunned to learn that fewer than a third complied with the advice. “If people don't respond to the lethal danger of unprotected sex with their husband or wife, we are in real trouble,” I thought. Over the next five years more than three quarters of the uninfected partners contracted HIV.
I have always used this experience as a guide to pit hope against reality. Human sexuality—the drive for sex and physical connection—is deeply embedded in our nature. I knew in the 1980s it was very unlikely people would change their sexual behavior in a major way. In the 19th century everyone knew how syphilis was contracted and that it was serious disease. Yet syphilis still infected at least 10 to 15 percent of American citizens at the beginning of the 20th century. It was not that people were ignorant of how to catch it; it is that they did not change their lifestyle accordingly.
There is likewise a sexual dynamic to COVID-19 that often goes unmentioned. It is part of what is driving people out of their homes and into bars and parties. Anyone with a craving for a beer can quench their thirst in the safety of their own home, but gratification comes less easily for other desires, especially when one is young, single and living alone. Our public health strategies should not ignore this fact.
The same lessons we learned in the midst of the HIV epidemic to help young people change their behaviors apply today to COVID-19: know your risk, know your partners and take necessary precautions. Many young people operate under the false assumption that even if they become infected, they will not become severely ill. Not only is this belief untrue, but even people with asymptomatic infections can suffer serious, lasting damage. But the more people understand the risk—younger people especially—the greater likelihood they will take the steps necessary to protect themselves and others. We saw this happen with AIDS.
Funding
When I ask world experts what they know about the detailed molecular biology of SARS-CoV-2 or, for that matter, any other coronavirus, they do not have the kind of answers they should. Why? Because governments and industry pulled the plug on coronavirus research funding in 2006 after the first SARS (severe acute respiratory syndrome) pandemic faded away and again in the years immediately following the MERS (Middle East respiratory syndrome, also caused by a coronavirus) outbreak when it seemed to be controllable. Funding agencies everywhere, not just in the U.S. but in China, Japan, Singapore, Hong Kong and the Middle East—countries affected by SARS and MERS—underestimated the threat of coronaviruses. Despite clear, persistent, highly vocal warnings from many of those who battled SARS and MERS up close, funding dried up. The development of promising anti-SARS and MERS drugs, which might have been active against SARS-CoV-2 as well, was left unfinished for lack of money.
With 776,000 dead and 22 million infected globally as of mid-August, we have every motive to accelerate funding. The U.S. quickly opened the funding spigots last spring for research to hasten discoveries of vaccines and drugs. But will it be enough?
We learned from the HIV crisis that it was important to have research pipelines already established. Cancer research in the 1950s, 1960s and 1970s built a foundation for HIV/AIDS studies. The government responded to public concerns, sharply increasing federal funding of cancer research during those decades. These efforts culminated in Congress's approval of President Richard Nixon's National Cancer Act in 1971. This $1.6-billion commitment for cancer research, equal to $10 billion in today's money, built the science we needed to identify and understand HIV in the 1980s, although of course no one knew that payoff was coming.
In the 1980s the Reagan administration did not want to talk about AIDS or commit much public funding to HIV research. The first time President Ronald Reagan gave a major speech on AIDS was in 1987. In his first administration, funding for HIV research was scarce; few scientists were willing to stake their careers on deciphering the molecular biology. Yet once the news broke that actor Rock Hudson was seriously ill with AIDS, Ted Stevens, the Senate Republican Whip, joined with Democratic Senator Ted Kennedy, actor Elizabeth Taylor, me and a few others in campaigning effectively to add $320 million in the fiscal 1986 budget for AIDS research. Barry Goldwater, Jesse Helms and John Warner, Republican leaders in the Senate, supported us. The money flowed, and outstanding scientists signed on. I helped to design this first congressionally funded AIDS research program with Anthony Fauci, the doctor now leading our nation's fight against COVID-19. (And if there is one person in the world who has made the greatest contribution to the prevention and treatment of AIDS, that person is Fauci.)
One difference between the 1980s and now is that Republican members of Congress were more willing to stand up to the president and White House staff when they failed to take the necessary steps to fight a global disease. For example, Stevens decided it was his job to protect the U.S. Army and other arms of the military and Secret Service as much as possible from HIV infection. He helped to move $55 million within the defense budget, designating it for screening recruits for HIV/AIDS.
Our tool set for virus and pharmaceutical research has improved enormously in the past 36 years since HIV was discovered. This is one reason I am confident we will have effective antiviral drugs for treating COVID-19 infections by next year, if not sooner. What used to take us five or 10 years in the 1980s and 1990s in many cases now can be done in five or 10 months. We can rapidly identify and synthesize chemicals to predict which drugs will be effective. We can do cryoelectron microscopy to probe virus structures and simulate molecule-by-molecule interactions in a matter of weeks—something that used to take years. The lesson is to never let down our guard when it comes to funding antivirus research. We would have no hope of beating COVID-19 if it were not for the molecular biology gains we made during earlier virus battles. What we learn this time around will help us out during the next pandemic, but we must keep the money coming.
A Leap into Darkness
In November 2019 I spent several days in Wuhan, China, chairing a meeting of the U.S.-China Health Summit. Our group's major concern, looming amid the U.S.-China trade war, was the threat of restrictions on sharing research discoveries. Otherwise, it was a delightful time in a beautiful city.
Weeks later, back home in New York City, I could not shake a lingering cold virus infection I picked up on the Wuhan trip. (I later tested negative for COVID-19 antibodies, but that result is not definitive.) The head of my foundation in China called me one day with awful news. Three of his grandparents had died from some strange virus. “Everyone who gets this is really sick,” my colleague, in his mid-30s, said. “Everything is closed down. I can't even go to my grandparents' funerals.”
A few weeks later I received a vivid firsthand account of how aggressively China was confronting the outbreak from another colleague who had just emerged from 14 days of isolation in a quarantine hotel. He explained that when one person in the back of his flight from Frankfurt, Germany, to Shanghai tested positive for the coronavirus, contact tracers called my friend days later and ordered him into isolation. His only human contact then was with hazmat-clad inspectors who came daily to disinfect his room and drop off meals.
We are just beginning to glimpse what the long-term toll of COVID-19 might be. This is a new virus, so we will not have a clearer idea until after a few years, but we know it will be very high. We have barely scratched the surface of coronavirus molecular biology. What story will our children and grandchildren recount about our successes as scientists and as a society, and our failures, to contain this pandemic—the worst we have faced in 100 years?
Science leaps into the darkness, the very edge of human knowledge. That is where we begin, as if deep in a cave, chipping away at a wall of hard stone. You do not know what you will find on the other side. Some people chip away for a lifetime, only to accumulate a pile of flakes. We may be in for a protracted pandemic, or we may get lucky with effective treatments and vaccines soon. But we have been here before, facing an unknown viral enemy, and we can lean on lessons we have learned. This is not the first and will not be the last global epidemic.
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