A new study in monkeys suggests that a blood test could predict the effectiveness of a Covid-19 vaccine — and perhaps speed up the clinical trials needed to get a working vaccine to billions of people around the world.
The study, published on Friday in Nature, reveals telltale blood markers that predict whether a monkey’s immune system is prepared to wipe out incoming coronaviruses.
The finding raises hope that researchers will be able to look for the same markers in people who get vaccines in clinical trials. If the markers are strong enough, they could reveal if the vaccines protect against Covid-19. And researchers would no longer have to wait for some trial volunteers to get the disease, as they do now.
“It will pave the way for a much more rapid advancement of the Covid vaccine field,” said Dr. Dan Barouch, a vaccine expert at Beth Israel Deaconess Medical Center in Boston and one of the researchers behind the new study.
Last month brought the stunning news that clinical trials of two new coronavirus vaccines, one from Moderna and the other from Pfizer and BioNTech, showed efficacy rates around 95 percent.
The strength of these two vaccines is, paradoxically, bad news for the dozens of others in earlier stages of development. Many of them will most likely have to be compared against the robust front-runners rather than a placebo shot. Because that is a high statistical bar to clear, their trials will need a lot more volunteers, time and money.
“You’d have to follow millions of people for a long time,” said Dr. Nelson Michael, the director of the Center for Infectious Diseases Research at Walter Reed Army Institute of Research, where a protein-based vaccine is being prepared for clinical trials in early 2021. “It’s just fantasy.”
For some smaller companies, these comparison trials may be deal-breakers. “You’re going to see a lot of dropout,” said Dr. Gregory Poland, a vaccine expert at the Mayo Clinic.
That’s a big problem, because Pfizer and Moderna won’t have nearly enough doses to give to everyone in the United States, let alone the world. And the next wave of vaccines may turn out to be superior to the first, in one way or the other. They could cost a lot less, for example. Some might come in just one dose instead of two, and won’t need a deep freeze. Some might offer protection that lasts a lot longer.
“We’d rather not have to revaccinate the world every one or two years,” Dr. Michael said.
The new monkey study offers a ray of hope for these next-generation vaccines, suggesting that they could be tested not against older vaccines, but using a measurement known as a “correlate of protection.”
“That’s the holy grail of vaccine research,” Dr. Michael said.
Influenza vaccines are already tested this way. Every new flu season requires the design of a new flu shot, but researchers don’t have to run clinical trials comparing it with old versions. Instead, they just check whether the new vaccine triggers a person’s immune system to make enough of a certain kind of antibody against the flu. If it does, then researchers know the vaccine is adequately stimulating the immune system.
If scientists could discover a correlate of protection against the coronavirus, they could follow the example of the flu. “That is an entirely plausible and feasible scenario,” said Dr. Anthony Fauci, the director of the National Institutes of Allergy and Infectious Diseases.
A spokeswoman for the Food and Drug Administration said that basing clinical trials on correlates of protection — if they turn out to exist — “possibly could be considered in the future.”
In their new study, Dr. Barouch and his colleagues found a correlate of protection in monkeys. They built the experiment on their previous research showing that once monkeys recover from Covid-19, they can resist a second infection. The scientists drew blood from these exposed animals and isolated an array of protective antibodies called IgG.
Confused by the all technical terms used to describe how vaccines work and are investigated? Let us help:
- Adverse event: A health problem that crops up in volunteers in a clinical trial of a vaccine or a drug. An adverse event isn’t always caused by the treatment tested in the trial.
- Antibody: A protein produced by the immune system that can attach to a pathogen such as the coronavirus and stop it from infecting cells.
- Approval, licensure and emergency use authorization: Drugs, vaccines and medical devices cannot be sold in the United States without gaining approval from the Food and Drug Administration, also known as licensure. After a company submits the results of clinical trials to the F.D.A. for consideration, the agency decides whether the product is safe and effective, a process that generally takes many months. If the country is facing an emergency — like a pandemic — a company may apply instead for an emergency use authorization, which can be granted considerably faster.
- Background rate: How often a health problem, known as an adverse event, arises in the general population. To determine if a vaccine or a drug is safe, researchers compare the rate of adverse events in a trial to the background rate.
- Efficacy: The benefit that a vaccine provides compared to a placebo, as measured in a clinical trial. To test a coronavirus vaccine, for instance, researchers compare how many people in the vaccinated and placebo groups get Covid-19. Effectiveness, by contrast, is the benefit that a vaccine or a drug provides out in the real world. A vaccine’s effectiveness may turn out to be lower or higher than its efficacy.
- Phase 1, 2, and 3 trials: Clinical trials typically take place in three stages. Phase 1 trials usually involve a few dozen people and are designed to observe whether a vaccine or drug is safe. Phase 2 trials, involving hundreds of people, allow researchers to try out different doses and gather more measurements about the vaccine’s effects on the immune system. Phase 3 trials, involving thousands or tens of thousands of volunteers, determine the safety and efficacy of the vaccine or drug by waiting to see how many people are protected from the disease it’s designed to fight.
- Placebo: A substance that has no therapeutic effect, often used in a clinical trial. To see if a vaccine can prevent Covid-19, for example, researchers may inject the vaccine into half of their volunteers, while the other half get a placebo of salt water. They can then compare how many people in each group get infected.
- Post-market surveillance: The monitoring that takes place after a vaccine or drug has been approved and is regularly prescribed by doctors. This surveillance typically confirms that the treatment is safe. On rare occasions, it detects side effects in certain groups of people that were missed during clinical trials.
- Preclinical research: Studies that take place before the start of a clinical trial, typically involving experiments where a treatment is tested on cells or in animals.
- Viral vector vaccines: A type of vaccine that uses a harmless virus to chauffeur immune-system-stimulating ingredients into the human body. Viral vectors are used in several experimental Covid-19 vaccines, including those developed by AstraZeneca and Johnson & Johnson. Both of these companies are using a common cold virus called an adenovirus as their vector. The adenovirus carries coronavirus genes.
- Trial protocol: A series of procedures to be carried out during a clinical trial.
The researchers set out to see if there was a level of IgG that reliably protected monkeys from Covid-19. If the IgG antibodies produced by vaccines were above that level, the vaccines could be judged effective.
To find that line, the researchers gave monkeys varying doses of antibodies, and then exposed them all to the coronavirus and watched how well they fought off the infection. In the monkeys with the weakest dose, the viruses multiplied much as they would in an ordinary animal.
But the monkeys that got a medium dose produced far fewer viruses. Some of them were able to wipe out the viruses altogether. At the highest dose, the monkeys were completely protected.
Until now, scientists relied on circumstantial evidence that suggested IgG antibodies were crucial to clearing coronavirus infections. The new study puts that idea to the test — and determines the threshold of IgG antibodies required to ward off an infection.
“This is the first time, to the best of my knowledge, that we’ve actually proven that antibodies protect,” Dr. Barouch said. “Everything else has been a statistical association.”
The experiment revealed that a modest amount of IgG antibodies turned out to be enough. That could be heartening news for vaccine developers, because even so-so vaccines may be able to cross the threshold.
Researchers are now starting to review the results of vaccine clinical trials to see if a correlate of protection like the one identified by Dr. Barouch and his colleagues in monkeys exists in people. “The study bodes well for the upcoming immune correlates studies,” said Holly Janes, a biostatistician at the Fred Hutchinson Cancer Institute in Seattle who was not involved in Dr. Barouch’s study.
Although it will take some time for those studies to produce solid results, Dr. Janes said preliminary hints made her optimistic.
“The emerging data do suggest that we could be gleefully surprised,” she said.
Rebecca Robbins contributed reporting.