Vaccine manufacturer Novavax began a late-stage trial of its shot in December and will have difficulty recruiting and maintaining participants.Credit: PA Images / Alamy
Global health researchers breathed a collective sigh of relief last month after countries in Europe, North America and elsewhere issued emergency permits for the first COVID-19 vaccines. But as the shots roll out, clinicians are trying to figure out how to evaluate dozens of other candidates who have been vaccinated earlier. It can be cheaper, have fewer side effects or be applied more easily than those currently in use – and this will strengthen the world’s supply of COVID-19 vaccines, which will ensure faster distribution to all countries.
The problem is that finding prospective participants for placebo-controlled clinical trials has become a challenge. In these trials, half of the volunteers receive a shot and half of the right thing, but neither participants nor researchers know who received the one until after the trial. People are less likely to get a placebo when they can get one of the various vaccines that are now approved, two of which contain COVID-19 with approximately 95% efficacy.
As it is, many people who have participated in placebo-controlled trials have already asked to drop out to ensure they are vaccinated.
“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 human trials. “Once you have an available vaccine,” he notes, “a placebo-controlled trial is no longer ethical or acceptable.”
Analysts expect first-generation vaccines to be widely available in the next 6-12 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 placebo comparisons. “The window is closing,” said immunologist Robin Shattock of Imperial College London, whose own COVID-19 vaccine is in the first phase of human testing at four locations in the south of England.
Source: The World Health Organization’s COVID-19 Candidate Vaccine Landscape
Currently, about 60 follow-up vaccine candidates are in human trials, and another 170 are in various stages of preclinical evaluation (see ‘Next-generation vaccinations’). Some are built on genetic technologies and, when injected, help to produce coronavirus proteins in the body that cause immunity. Others contain coronavirus proteins, inactivated forms of the virus, or other types of viruses adapted to contain genetic instructions for making coronavirus proteins. “Globally,” says Shattock, “those who will achieve long-term stability are going to be the most stable and cost-effective.”
Recruitment Challenges
The massive deployment of vaccines to certain populations is already putting pressure on the recruitment of trials. For example, Novavax, a vaccine company in Gaithersburg, Maryland, is testing a vaccine that uses purified viral proteins, an established approach that offers potential safety benefits. Such vaccines can also be stored in refrigerators, which can be distributed through standard supply channels for vaccines. But in a trial of 30,000 people launched by Novavax late last month, health workers – a key target of earlier studies on vaccine efficacy due to their increased risk of infection – are according to Gregory Glenn, the company’s research and development chief. This is because many first generation receive shots.
And older people or people with underlying medical conditions – especially two groups that need vaccines because of their susceptibility to serious complications due to COVID-19 – may become increasingly difficult to report. This will be especially the case if governments follow the lead of U.S. states like Florida and Texas and make these groups eligible for vaccination. Taking these groups out of the pool of potential participants in the trial will make recruitment more difficult, “said C. Mary Healy, an infectious disease specialist at Baylor College of Medicine in Houston, Texas, who is involved in the Novavax study.
Trial designers have devised some solutions to encourage participation. In some placebo-controlled studies, for example, two people receive active vaccinations for everyone who gets a shot, instead of the usual proportionality. The approach enables businesses to gather more safety information about trial products. This is because more participants are receiving an active dose and thus may experience adverse reactions. As an added bonus, prospective students are more willing to ‘throw a dice if it’s a two-in-three chance’ that they will get a real chance, says Colleen Kelley, an infectious disease specialist at Emory University School. of Medicine. in Atlanta, Georgia, and a site investigator for the Novavax trial, using the randomization strategy.
Another solution is a trial in which no placebos are involved, and a vaccine is compared to an already authorized one. French vaccine manufacturer Sanofi Pasteur and its UK partner GlaxoSmithKline are working on a protein-based vaccine like that of Novavax, and they are now planning studies with such a design. According to unpublished calculations from the biostatistical group of the US Government’s Operation Warp Speed Vaccination Program, proving that an experimental vaccine is not significantly inferior to one that is 95% effective will usually require trials that are longer and larger than placebo. controlled studies. .
“They will have to be so large that they are unlikely to be practical,” says Peter Smith, an epidemiologist at the London School of Hygiene and Tropical Medicine.
Power of attorney protection
Another option, therefore, is to measure the effectiveness of a vaccine by using immune markers that a person develops in their blood after vaccination. These are signs – a certain level of antibodies, for example – whether the immune system is primarily to eradicate incoming coronaviruses.
New vaccinations for flu, rabies and many other infectious diseases are already being evaluated1 the use of these ‘correlates of protection’, and this removes the need for placebos. The problem for COVID-19 vaccine developers is that, unlike the diseases, it is not yet clear what kind of immune response is a reliable indicator of the protection of the vaccine against the coronavirus.
Experiments so far suggest that levels of an antibody called immunoglobulin G (IgG) may serve as the proxy indicator, but the evidence is only cumbersome, says Dan Barouch, a virologist at Beth Israel Deaconess Medical Center in Boston, Massachusetts. . To confirm IgG as a correlate of protection, scientists need to study people who have received a COVID-19 vaccine but then become ill anyway – which is called a breakthrough infection. If the level of IgG in human blood falls below a threshold found in people for whom the vaccines have worked, it may help scientists determine the amount of antibody needed to effectively evaluate any new vaccine.
Sick minded
Every major vaccine trial currently underway tests people’s blood for possible correlates of protection. Yet, with so few breakthrough cases in many of the first generation trials – only 11 in the study by the American biotechnology company Moderna2 and 8 in the study of drug giant Pfizer and German biotechnology firm BioNTech3 during primary analysis – researchers will probably have to combine data on studies and vaccination platforms to get answers.
A further complication is that most major vaccine trials are designed to test whether participants develop symptoms of COVID-19, rather than whether they are infected by the coronavirus. But if vaccines want to stop the spread of the virus, developers will need an immune correlate that indicates that a person is protected from infection, not just symptoms. This is something that is being actively investigated, but only by alternating measurements that, according to Holly Janes, a biostatistician at the Fred Hutchinson Cancer Research Center in Seattle, Washington, can “miss infections”.
Some researchers argue that vaccinated individuals are deliberately exposed to coronavirus in ‘human challenges’ trials and then closely monitor the infection rates and their associated biomarkers. The approach usually still involves placebos, but it requires far fewer volunteers than field trials and yields much faster results. Challenge trials remain controversial – even unethical, some say. But purely on a scientific level, everyone agrees that it is the best way to get accurate immune correlates, says Nir Eyal, a bioethicist at Rutgers University in New Brunswick, New Jersey, and a proponent of the strategy.
Regulatory agencies work closely with scientists and vaccine companies to determine the best path of development for the next generation of vaccines. “We’re in this funny area right now,” said Rob Coleman, co-founder and CEO of Codagenix, a company in Farmingdale, New York, which will begin human testing next week with a candidate for the COVID-19 vaccination that ‘ an attenuated form of the coronavirus. “There is no clear guidance.”