Enlarge /. A volunteer will receive an injection from a medical worker during the country's first clinical trial for a potential COVID-19 vaccine at Baragwanath Hospital on June 28, 2020 at the Baragwanath Hospital in Soweto, South Africa. Africa's first COVID-19 vaccine study is reported to have started in South Africa on June 24. The vaccine, developed by the Jenner Institute at Oxford University (UK), will vaccinate 2,000 South Africans.
Getty | Felix Dlangamandla
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Researchers have now reported data from early (and small) clinical trials with four candidate COVID-19 vaccines.
So far, the data are positive. The vaccines appear to be generally safe and spur immune responses to the novel SARS-CoV-2 coronavirus. However, whether these immune responses are sufficient to protect people from infections and diseases remains an important unknown.
The four candidates are now facing larger studies – phase III studies – that will put them to the ultimate test: can they protect people from COVID-19 and end this pandemic?
While dozens or hundreds of volunteers were required for early safety and immune response studies, researchers now have to recruit tens of thousands. Ideally, there are volunteers in places where there is still a high SARS-CoV-2 level in circulation. The more likely it is that volunteers will encounter the virus in their communities, the easier it will be to extrapolate whether a vaccine is protective. For this reason, researchers plan to conduct a significant number of tests in the U.S. and other parts of America that have largely failed to fight the pandemic.
There has been much debate over the use of Human Challenge Trials, in which researchers would give young, healthy, low-risk volunteers of COVID-19 an experimental vaccine and then intentionally expose them to SARS-CoV-2 in controlled environments. This could potentially provide a clearer and faster response to the effectiveness of the vaccine. Given the catastrophic pandemic, this is certainly an appealing idea – and this idea has grown in importance in recent weeks. For example, an advocacy group called 1Day Sooner has collected the names of more than 30,000 people who are willing to participate in such a process.
However, experts continue to disagree. The main concern is that there is no “rescue treatment” for COVID-19 that can fully protect a subject from serious illnesses and deaths if an experimental vaccine fails. Although young, healthy people are at lower risk than older people and people with underlying health conditions, some still suffer from serious illnesses and deaths from COVID-19 – and it is unclear why. Opponents also note that challenge attempts may not be faster or more necessary given the high spread of disease in the US and elsewhere.
Although the debate about attempted challenges is not yet over, it is unclear whether researchers will ultimately need or use it. Traditional Phase III studies are now underway – and they have generated a lot of public enthusiasm. According to a report this week, more than 138,600 people have signed up through the National Institutes of Health to take vaccine tests. If all goes well, we could have data from these studies by the end of the year.
How do the four best vaccine candidates work and what do we know about them?
mRNA-1273: Moderna, NIAID
mRNA-1273 is a messenger RNA (mRNA) vaccine from the biotechnology company Moderna, which has worked with the NIH's National Institute for Allergy and Infectious Diseases (NIAID). The idea behind the mRNA vaccine platform is that it delivers clippings of the genetic code of a target virus – in this case code in the form of mRNA – into human cells. These cells can then translate this code into viral protein. From there, the immune system can trigger a reaction to the protein, which can be activated if the target virus ever tries to enter.
In the case of mRNA-1273, the researchers used a fat nanoparticle to package mRNA that encodes the SARS-CoV-2 spike protein that normally protrudes from SARS-CoV-2 virus particles.
Vaccines with genetic material – RNA or DNA – are new and untested. So far there are no approved vaccines for this type of platform. It is unclear whether they will be successful here or elsewhere and – if so – how easy it will be to produce such a vaccine worldwide. (For background information on the different types of vaccine platforms, see our vaccine primer.)
On July 14, the researchers published the results of a phase 1 study, which primarily examined the safety of a small group of people. The study, which was published in the New England Journal of Medicine, included 45 healthy volunteers between the ages of 18 and 55 and tested three dose levels of the vaccine. That is, there were three groups of 15 people, with each group receiving either a low, medium, or high dose of the vaccine (25 micrograms, 100 micrograms, or 250 micrograms dose). Each participant received two shots of his dose 28 days apart.
The vaccine was generally found to be safe. More than half of the participants had mild to moderate side effects, including fatigue, chills, headache, myalgia, and pain at the injection site. Side effects were more common after the second dose, regardless of strength, but those who received the two higher dose vaccinations reported more side effects. Two people (one in the 100 microgram group and the other in the 250 microgram group) had severe skin redness at the injection site. Two people in the 250 microgram group were light-headed and passed out.
All participants produced antibodies against SARS-CoV-2, with antibody levels rising after the second shot. Those who received the higher doses had slightly higher antibody levels. The researchers compared the participants' antibody levels to those of 41 people who had recovered from COVID-19 infection. All vaccinated patients had antibodies in the same area as the salvaged people.
The researchers also specifically tested for neutralizing antibodies, ie antibodies that not only bind to a virus particle, but can completely deactivate it. The researchers found that the vaccine raised higher levels of neutralizing antibodies than most people who recovered. For example, 57 days after the first dose, people in the 100 microgram group had neutralizing antibody titers in the range of 163 to 329, while the range for those recovering from COVID-19 was about 60 to 200.
Most recently, the researchers examined the responses of T cells that can attack cells infected with viruses and found that the vaccine produced certain types of T cell responses to SARS-CoV-2.
Overall, the results are encouraging but not conclusive. Researchers do not yet know what immune responses or antibody levels are required to prevent SARS-CoV-2 infection and / or disease. And after just six months, the pandemic is unclear how long such protective immune responses would last.
According to a listing in the NIH Clinical Trial Register, Moderna plans to begin a Phase III trial of mRNA-1273 on July 27. Moderna plans to enroll 30,000 people to study efficacy and other safety and immune response data.
AZD1222 (ChAdOx1 nCoV-19): Oxford University, AstraZeneca
On July 20, the researchers released the results of a phase I / II trial of AZD1222, a vaccine candidate made by researchers from Oxford University and the international pharmaceutical company AstraZeneca.
AZD1222 (also called ChAdOx1 nCoV-19) is a vaccine based on viral vectors. This platform enables researchers to pack parts of a dangerous virus into a far less dangerous virus. The mostly harmless virus package is then delivered to the immune system, which can learn to search for and destroy the dangerous virus using the smuggled fragments.
In the case of AZD1222, genetic material of the SARS-CoV-2 spike protein is packaged in a weakened type of adenovirus that infects chimpanzees. Human-infecting adenoviruses usually cause mild infections, which are often considered colds. The chimpanzee virus, which normally does not infect humans, is made even more harmless by a technique that prevents it from replicating in human cells. In early tests, AZD1222 protected monkeys from pneumonia after the researchers exposed them to high doses of SARS-CoV-2.
Clinical trial results published in The Lancet show that AZD1222 is generally safe in humans and triggers immune responses. The study included 1,077 participants (ages 18 to 55), 543 of whom received AZD1222 at random, and the remaining 534 received a meningococcal vaccine as a control. The researchers divided the participants into four groups and performed different types of tests for their immune responses. Ten of the participants who received AZD1222 belonged to a “boost” group that received a second shot of vaccine after 28 days. The other participants who received AZD1222 received only one dose.
Mild side effects from AZD1222 were common, including pain, fever, chills, muscle aches, headaches, and malaise. Some participants received preventive paracetamol (paracetamol / tylenol) to reduce these effects. No serious side effects have been reported.
In 127 participants vaccinated with AZD1222, all produced antibodies against SARS-CoV-2. The values were within the range observed in people who had recovered from COVID-19. The researchers performed two separate tests to look for neutralizing antibodies in 35 vaccinated participants. In one test, 32 (91 percent) 28 days after vaccination were positive for antibody neutralization and in the other test 100 percent were positive. The ten participants who received a booster shot all produced neutralizing antibodies, some of which were higher than those typically seen in COVID-19 patients. The researchers also reported that AZD1222 induced T cell responses.
Researchers have already started a Phase III trial with AZD1222 at sites in Brazil, the UK and South Africa. They are also planning to test the vaccine in the US soon. AstraZeneca said it will use two doses in future studies to maximize immune responses.