How and when will we know that a COVID-19 vaccine is safe and effective ?

    28-Sep-2020
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William Petri
With COVID-19 vaccines currently in the final phase of study, you’ve probably been wondering how the FDA will decide if a vaccine is safe and effective.
Based on the status of the phase 3 trials currently underway, it is unlikely that the results of these trials will be available before November. But it is likely that not just one but several of the competing COVID-19 vaccines will be shown to be safe and effective by the end of 2020.
I am a scientist and infectious diseases specialist at the University of Virginia, where I care for patients with COVID-19 and conduct research on the pandemic. I am also a member of the World Health Organisation Expert Group on COVID-19 Vaccine Prioritisation.
What is the status of COVID-19 vaccines in human clinical trials?
Phase 3 studies are underway for the Moderna and BioNTech/Pfizer vaccines, the Oxford/AstraZeneca viral vector vaccine and now the Johnson & Johnson viral vector vaccine.
Each of these vaccines uses the SARS-CoV-2 spike glycoprotein, which the virus uses to infect cells, to trigger the immune system to generate protective antibodies and a cellular immune response to the virus. Protective antibodies act by preventing the spike glycoprotein from attaching the virus to human cells, thereby neutralising the SARS-CoV-2 virus that causes COVID-19.
In the case of Moderna’s nucleic acid vaccine, the messenger RNA encoding the spike glycoprotein is encased in a fat droplet – called a liposome – to protect the mRNA from degradation and enable it to enter cells. Once these instructions are inside the cells, the mRNA is read by the human cell machinery and made into many spike proteins so that the immune system can respond and begin producing antibodies against this coronavirus.
The Oxford/AstraZeneca and Johnson & Johnson vaccines use a different strategy to activate an immune response. Here an adenovirus found in chimpanzees shuttles the instructions for manufacturing the spike glycoprotein into cells.
Phase 1 and 2 studies by pharmaceutical companies Janssen and Merck also use viral vectors similar to the Oxford/AstraZeneca and J&J vaccines, while vaccines by Novavax and GSK-Sanofi use the actual spike protein itself.
Animal tests show the vaccines provide protection from coronavirus infection
Studies in animal models of COVID-19 provide convincing evidence that vaccination with the spike glycoprotein will protect from COVID-19. Experiments have shown that when the immune system is shown the spike protein – which alone cannot trigger disease – the immune system will generate an antibody response that protects from infection with SARS-CoV-2.
In studies in hamsters an adenovirus viral vector – the approach used by Oxford/AstraZeneca, for example – was used to immunise with the spike glycoprotein. When the hamsters were infected with SARS-CoV-2 they were protected from pneumonia, weight loss and death.
In nonhuman primates, DNA vaccines – which deliver the gene for the spike glycoprotein – reduced the amount of virus in the lungs. Animals that produced antibody that prevented virus attachment to human cells were most likely to be protected.
What have the early Phase 1 and 2 studies in humans shown?
Overall, vaccination has triggered a more potent neutralising antibody response than even that seen in patients recovering from COVID-19.
This has also been the case for Moderna’s vaccine currently in phase 3 trials and for vaccines from CanSino Biologics and Oxford/ AstraZeneca.
What side effects have been observed ?
Physicians have recorded mild to moderate reactions when the subjects were observed up to 28 days after vaccination. These side effects included mild pain, warmth and tenderness at the site of injection, and fever, fatigue, joint and muscle pain. But Phase 1 and 2 studies are small by design, with just hundreds of participants. So these trials will not be large enough to detect uncommon or rare side effects.
The emphasis on safety as the primary goal was recently demonstrated in the Phase 3 Oxford/AstraZeneca vaccine trial where one vaccinated individual developed inflammation of the spinal cord. It isn’t clear whether the vaccine caused this reaction – it might be a new case of multiple sclerosis unrelated to the vaccine – but the phase 3 trial was halted in the US until more is known.
(To be contd)