Search for better COVID vaccines confused by existing implementations

Global health researchers breathed a collective sigh of relief last month after nations in Europe, North America and elsewhere issued emergency approvals of the first COVID-19 vaccines. But as injections are launched, doctors are struggling to figure out how to evaluate dozens of other early-stage vaccine candidates. They could be cheaper, have fewer side effects, or be easier to administer than those in use – and would increase the global supply of COVID-19 immunizations, ensuring faster distribution to all countries.

The problem is that finding possible participants for placebo-controlled clinical trials has become a greater challenge. In these tests, half of the volunteers receive a simulated injection and the other half a real injection, but neither the participants nor the researchers know who received which one until after the test. People are less likely to receive a placebo when they can receive one of several vaccines now authorized, two of which prevent COVID-19 with about 95% effectiveness.

As it stands, many people participating in placebo-controlled studies have already asked to give up to ensure they would be immunized.

“The landscape is changing,” says Scott Halperin, director of the Canadian Center for Vaccinology at Dalhousie University in Halifax, who is leading the testing of two COVID-19 vaccines in humans. “Once you have a vaccine available,” he notes, “a placebo-controlled trial is no longer ethical or acceptable.”

Analysts expect first generation vaccines to be widely available in the next 6 to 12 months in most high-income countries and in some parts of the developing world. Next-generation vaccine manufacturers are therefore considering ways to prove the effectiveness of their products without comparisons to placebo. “The window is closing,” says immunologist Robin Shattock of Imperial College London, whose own COVID-19 vaccine is in its first phase of human testing at four sites in southern England.

At present, about 60 continuation candidate vaccines are being tested in humans and another 170 are in various stages of pre-clinical evaluation (see ‘Next generation vaccines’). Some are built based on genetic technologies and, when injected, help to produce coronavirus proteins within the body that activate immunity. Others contain coronavirus proteins, inactivated forms of the virus, or other types of viruses modified to carry genetic instructions for the production of coronavirus proteins. “On a global level,” says Shattock, “those who will win in the long run will be those who will be most stable and economical.”

Recruitment challenges

The mass distribution of vaccines to certain populations is already beginning to hamper testing recruitment. For example, Novavax, a vaccine company in Gaithersburg, Maryland, is testing a vaccine that uses purified virus proteins, an established approach that offers potential safety benefits. These vaccines can also be stored in refrigerators, allowing distribution through standard vaccine supply chain channels. But in a test of 30,000 people launched by Novavax at the end of last month, healthcare professionals – one of the main targets of previous vaccine efficacy studies due to their high risk of infection – are no longer highly sought after recruits, according to Gregory Glenn, the company’s research and development chief. That’s because many are receiving photos of the first generation.

And older individuals or people with underlying medical conditions – two groups in particular need vaccines because of their susceptibility to serious complications from COVID-19 – can become increasingly difficult to enroll. This will be especially the case if governments follow the example of US states, such as Florida and Texas, and make these groups eligible for vaccination. Removing these groups from the pool of potential trial participants “will inevitably make recruitment more challenging,” says C. Mary Healy, an infectious disease specialist at Baylor College of Medicine in Houston, Texas, who is involved in the Novavax study.

Test designers have developed some alternative solutions to encourage participation. In some placebo-controlled studies, for example, two people receive active vaccines for each one who receives a dummy injection, instead of the usual uniform division. The approach allows companies to collect more safety information about test products. This is because more participants receive an active dose and, therefore, may experience adverse reactions. As an added bonus, prospective study participants are more willing to “roll the dice if there are two out of three chances” to receive a real chance, notes Colleen Kelley, an infectious disease specialist at Emory University School of Medicine in Atlanta, Georgia , and a local investigator for the Novavax study, who is using the randomization strategy.

Another workaround is a trial in which no placebos are involved and, instead, a vaccine is compared to one already authorized. French vaccine manufacturer Sanofi Pasteur and its British partner GlaxoSmithKline are working on a protein-based vaccine similar to that of Novavax, and are now planning studies with this type of project. But, according to unpublished calculations by the US government’s Operation Warp Speed ​​vaccine program biostatistics group, proving that an experimental vaccine is not substantially less than one that is 95% effective usually requires trials that are longer and larger than placebo-controlled studies.

“They would need to be so big that they probably wouldn’t be practical,” says Peter Smith, an epidemiologist at the London School of Hygiene and Tropical Medicine.

Protection proxy

Another option, therefore, is to measure the effectiveness of a vaccine using immunological markers that a person develops in his blood after inoculation. These are telltale signs – a certain level of antibody, say – that the immune system is prepared to eliminate incoming coronaviruses.

New vaccines for flu, rabies and many other infectious diseases are already evaluated¹ using these ‘protective correlates’, and this eliminates the need for placebos. The problem for developers of the COVID-19 vaccine is that, unlike the case with these diseases, it is not yet clear what type of immune response is a reliable indicator of protection induced by the vaccine against coronavirus.

Tests so far suggest that levels of an antibody called immunoglobulin G (IgG) may serve as a proxy indicator, but the evidence is only circumstantial, says Dan Barouch, a virologist at Beth Israel Deaconess Medical Center in Boston, Massachusetts. To confirm IgG as a protective correlate, scientists need to study people who have received a COVID-19 vaccine, but then fall ill anyway – developing what are called revolutionary infections. If the level of IgG in their blood falls below a threshold found in people for whom the vaccines have worked, it could help scientists determine the amount of antibody needed for any new vaccine to be considered effective.

Unwell

All major vaccine trials underway are testing people’s blood for potential protection correlates. However, with so few innovative cases in many of the first generation tests – only 11 in the study by the modern American biotechnology company^two and 8 in the study by pharmaceutical giant Pfizer and the German biotechnology company BioNTech³ during primary analysis – researchers are likely to have to gather data across studies and vaccine platforms to get answers.

An additional complication is that most large vaccine trials are designed to test whether participants develop symptoms of COVID-19, rather than whether they were infected with the coronavirus. But in order for vaccines to stop the virus from spreading, developers will require an immune correlate indicating that the person is protected from infection, not just symptoms. This is something that is being actively investigated, but only through intermittent measurements that, according to Holly Janes, a biostatistics at Fred Hutchinson Cancer Research Center in Seattle, Washington, “can pass infections on.”

Some researchers argue for the deliberate exposure of individuals vaccinated to the coronavirus in “human challenge” tests and then carefully track infection rates and their associated biomarkers. The approach still involves placebos, but requires far fewer volunteers than field tests and produces results much more quickly. Challenge trials remain controversial – even unethical, some say. But, purely on a scientific level, everyone agrees that they are the best way to obtain accurate immunological correlates, notes Nir Eyal, a bioethicist at Rutgers University in New Brunswick, New Jersey, and an advocate of strategy.

Regulatory agencies are now working with scientists and vaccine companies to determine the best development path for next generation vaccines. “We are in that funny zone right now,” says Rob Coleman, co-founder and chief executive of Codagenix, a company in Farmingdale, New York, which is due to begin human testing next week with a candidate vaccine COVID-19 that contains a form of coronavirus. “There is no clear direction.”