If you think vaccination is an ordeal now, consider the 18th-century version. After having pus from a smallpox boil scratched into your arm, you would be subject to three weeks of fever, sweats, chills, bleeding and purging with dangerous medicines, accompanied by hymns, prayers and hell-fire sermons by dour preachers.
That was smallpox vaccination, back then. The process generally worked and was preferred to enduring “natural” smallpox, which killed around a third of those who got it. Patients were often grateful for trial-by-immunization — once it was over, anyway.
“Thus through the Mercy of God, I have been preserved through the Distemper of the Small Pox,” wrote one Peter Thatcher in 1764, after undergoing the process in a Boston inoculation hospital. “Many and heinous have been my sins, but I hope they will be washed away.”
Today, Americans are once again surprisingly willing, even eager, to suffer a little for the reward of immunity from a virus that has turned the world upside down.
Roughly half of those vaccinated with the Moderna or Pfizer-BioNTech vaccines, and in particular women, experience unpleasantness, from hot, sore arms to chills, headache, fever and exhaustion. Sometimes they boast about the symptoms. They often welcome them.
Suspicion about what was in the shots grew in the mind of Patricia Mandatori, an Argentine immigrant in Los Angeles, when she hardly felt the needle going in after her first dose of the Moderna vaccine at a March appointment.
A day later, though, with satisfaction, she “felt like a truck hit me,” Mandatori said. “When I started to feel rotten I said, ‘Yay, I got the vaccination.’ I was happy. I felt relieved.”
While the symptoms show your immune system is responding to the vaccine in a way that will protect against disease, evidence from clinical trials showed that people with few or no symptoms were also protected. Don’t feel bad if you don’t feel bad, the experts say.
“This is the first vaccine in history where anyone has ever complained about not having symptoms,” said immunologist Dr. Paul Offit, director of the Vaccine Education Center at Children’s Hospital of Philadelphia.
But that doesn’t mean people who don’t react to the vaccine severely are less protected, said Dr. Joanna Schaenman, an expert on infectious diseases and the immunology of aging at the David Geffen School of Medicine at UCLA. While the symptoms of illness are undoubtedly part of the immune response, the immune response that counts is protection, she said. “That is preserved across age groups and likely to be independent of whether you had local or systemic side effects or not.”
The immune system responses that produce post-vaccination symptoms are thought to be triggered by proteins called toll-like receptors, which reside on certain immune cells. These receptors are less functional in older people, who are also likely to have chronic, low-grade activation of their immune systems that paradoxically mutes the more rapid response to a vaccine.
But other parts of their immune systems are responding more gradually to the vaccine by creating the specific types of cells needed to protect against the coronavirus. These are the so-called memory B cells, which make antibodies to attack the virus, and “killer T cells” that track and destroy virus-infected cells.
Many other vaccines, including those that prevent hepatitis B and bacterial pneumonia, are highly effective while having relatively mild side effect profiles, Schaenman noted.
Whether you have a strong reaction to the vaccine “is an interesting but, in a sense, not vital question,” said Dr. William Schaffner, a professor of infectious disease at Vanderbilt University Medical Center. The bottom line, he said: “Don’t worry about it.”
There was a time when doctors prescribed cod-liver oil and people thought medicine had to taste bad to be effective. People who get sick after covid vaccination “feel like we’ve had a tiny bit of suffering, we’ve girded our loins against the real thing,” said Schaenman (who had a slight fever). “When people don’t have the side effects, they feel they’ve been robbed” of the experience.
Still, side effects can be a hopeful sign, especially when they end, says McCarty Memorial Christian Church leader Eddie Anderson, who has led efforts to vaccinate Black churchgoers in Los Angeles. He helps them through the rocky period by reminding them of the joyful reunions with children and grandchildren that will be possible post-vaccination.
“I’m a Christian pastor,’’ he said. “I tell them, ‘If you make it through the pain and discomfort, healing is on the other side. You can be fully human again.”
Although scientists and stock markets have celebrated the approval for emergency use of remdesivir to treat COVID-19, a cure for the disease that has killed nearly 260,000 people remains a long way off — and might never arrive.
Hundreds of drugs are being studied around the world, but “I don’t see a lot of home runs right now,” said Dr. Carlos del Rio, a professor of infectious diseases at the Emory University Rollins School of Public Health. “I see a lot of strikeouts.”
Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, was cautious when announcing the results of a clinical trial of remdesivir last week, noting it isn’t a “knockout.” Although remdesivir helped hospitalized COVID-19 patients recover more quickly, it hasn’t been proved to save lives.
“This [drug] is opening the door,” Fauci said. “As more companies and investors get involved, it’s going to get better and better.”
In future trials, researchers plan to combine remdesivir with other experimental drugs to try to improve its results, Fauci said.
But COVID-19 is an elusive enemy.
Doctors treating COVID patients say they’re fighting a war on multiple fronts, battling a virus that batters organs throughout the body, causes killer blood clots and prompts an immune system overreaction called a “cytokine storm.”
With so many parts of the body under siege at once, scientists say, improving survival rates will require multiple routes of attack — and more than one drug. While some of the experimental medications target the virus, others aim to prevent the immune system from inflicting collateral damage.
“There are so many pieces of this, and they will all require different therapies,” said Dr. Lewis Kaplan, president of the Society of Critical Care Medicine, whose doctors provide intensive care.
Some doctors are skeptical that drugs for heartburn or hot flashes have any chance of treating a killer like COVID-19.
Dr. Steven Nissen, chair of cardiovascular medicine at the Cleveland Clinic, said he fears that hype over unproven products will harm patients, even if it temporarily boosts company stock prices. Patients who demand antacids or antimalarial drugs being studied in COVID-19 could be harmed by side effects, for example. Those who hoard drugs — on the hope of protecting themselves from COVID-19 — could deprive other patients of medications they need to stay healthy. Some people may refuse to participate in clinical trials because they fear being given a placebo.
“This rush to get every imaginable treatment into a study, it’s not prudent,” Nissen said. “It’s not good medicine. It’s an act of desperation.”
Other experts say scientists should cast a wide net.
“I don’t think we want to rule anything out because it sounds out of the ordinary,” said Dr. Walid Gellad, director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh.
Antivirals In The Spotlight
Antivirals such as remdesivir aim to prevent viruses from replicating, said Dr. Peter Hotez, a professor at Baylor College of Medicine in Houston.
That doesn’t always work. A small Chinese study of remdesivir, published last month in The Lancet, found no benefit to severely ill COVID-19 patients. Remdesivir had previously failed when tested against Ebola.
Antivirals tend to be most helpful in the early stages of infection, when most of the harm to the patient is caused by the virus itself, rather than the immune system, Hotez said.
Remdesivir is just one of many antivirals being tested against COVID-19.
International researchers are studying the antiviral favipiravir, developed to fight the flu.
A study in the New England Journal of Medicine likewise found no benefit in giving two antivirals used to treat HIV ―a combination of lopinavir and ritonavir, sold as Kaletra— in adults hospitalized with severe COVID-19.
Harnessing The Immune System
One of the therapies generating excitement is also one of the oldest: antibody-rich blood from COVID survivors.
The immune system produces antibodies in response to invaders such as viruses and bacteria, allowing the body to recognize and neutralize them. Antibodies also recognize and neutralize the virus the next time that person is exposed.
Doctors hope that patients who develop antibodies against the novel coronavirus will become immune, at least for a few years, although this hasn’t been proved.
Scientists developing this “convalescent plasma” are studying whether COVID-19 survivors can share this immunity with others by donating their plasma, the liquid part of blood that contains antibodies, said Dr. Shmuel Shoham, an associate professor of medicine at the Johns Hopkins University School of Medicine.
In addition to treating people who are already sick, donated plasma could potentially prevent people exposed to the virus — such as health care workers — from developing symptoms.
Donated antibodies ― and any immunity they might provide — don’t last forever, said Dr. William Schaffner, a professor at the Vanderbilt University Medical Center. The body destroys aging antibodies as part of its routine maintenance, he said. In general, half of donated antibodies are eliminated in about three weeks.
Doctors don’t know yet whether convalescent plasma will benefit people with COVID-19.
In general, convalescent plasma is expected to be more effective in preventing illness than in treating it. It may be less likely to help someone in intensive care, Shoham said.
Researchers are also studying the use of prepackaged plasma, called intravenous immunoglobulin, in COVID patients. This product, known as IVIG, is taken from healthy donors in the general population and has long been used to help patients with weakened immune systems fight off infections. Hospitals keep it in stock and some are already using it to treat COVID patients.
Although the antibodies in prepackaged IVIG don’t specifically target the coronavirus, researchers hope they will tamp down the immune response.
In a third form of immune therapy, researchers are trying to identify the specific antibodies that are most important for neutralizing the coronavirus, then reproduce them as drugs called monoclonal antibodies. Monoclonal antibodies are already used to treat a variety of conditions, from cancer to rheumatoid arthritis and migraines.
“When we give people an antibody, they are immediately at least partially immune to that specific virus,” said Dr. James Crowe, director of the Vanderbilt Vaccine Center, who hopes to have antibodies ready for a clinical trial in a few months. “We’re moving the immune system from one person to another.”
Ideally, doctors would develop a very potent monoclonal antibody or a cocktail of antibodies for COVID-19 patients, to ensure the best chance of success, Crowe said. But manufacturing these drugs can be complicated, expensive and time-consuming.
“Making two antibodies would be at least twice as complicated as making one,” Crowe said. “A cocktail might be preferred, but cocktails are harder to move quickly.”
Calming The Immune System
In most cases of COVID-19, the immune system neutralizes the coronavirus and patients recover without going to the hospital.
For reasons that doctors don’t totally understand, the immune system of some COVID-19 patients becomes hyperactive, attacking not just the virus but the patient’s own cells. A “cytokine storm,” in which the immune system floods the body with inflammatory chemicals, can do more damage than the virus itself.
In an effort to calm the immune system, researchers are testing immune-suppressing drugs, including monoclonal antibodies already used to treat autoimmune diseases such as rheumatoid arthritis, said Dr. Amesh Adalja, a senior scholar at the Johns Hopkins Center for Health Security.
Health care giant Roche is conducting large clinical trials of its drug, Actemra, in the hope of preventing cytokine storms, which can cause organ failure and a life-threatening condition called sepsis. Actemra is designed to lower levels of an inflammatory chemical, interleukin-6, which has been found to be elevated in some COVID-19 patients.
Another immune suppressant from Regeneron and Sanofi, called Kevzara, has had disappointing results in clinical trials. The manufacturers plan to continue studying the drug to see if it can help certain types of patients.
Dr. Anar Yukhayev, a New York OB-GYN who was hospitalized with COVID-19 on March 16, agreed to join a clinical trial of Kevzara.
“I was having so much trouble breathing that I was desperate for anything to help,” said Yukhayev, 31, who was treated at Long Island Jewish Medical Center.
About 36 hours after receiving an infusion, as Yukhayev was being treated in intensive care, his symptoms began to improve. He was able to avoid being put on a ventilator. Doctors didn’t tell him if he received Kevzara or a placebo, but his liver enzymes also began to rise, suggesting the organ was under stress. Elevated liver enzymes are a known side effect of Kevzara.
Yukhayev made a full recovery and went back to work full time April 13. He donated his plasma to researchers.
Until vaccines and other preventive medicines are developed, the best way to prevent coronavirus infections is to maintain social distancing, Adalja said.
“Social distancing is a blunt tool,” he said, “but it’s all that we have.”