Making Sense of Medical Science (MSMS)

At last tally 197 vaccine candidates against the CoV-2 virus are being developed around the world. On May 12, that number was 125. It seems that vaccine candidates are spreading as fast as the virus. According to the World Health Organization, 23 of these experimental vaccines already are in human trials. As reported two months ago in these pages, the vaccine that seems to have the early lead is being developed at England’s Oxford University in partnership with the pharma company AstraZeneca. On Monday, they reported encouraging results from their combination phase 1/2 study in the journal The Lancet.

The Jenner Institute, Oxford University

It also seems that two other vax candidates have caught up to the Oxford efforts and also have reported encouraging results in early combination phase 1/2 or phase 2 studies. One of the vaccines is being developed by the Chinese company CanSino Biologics, which also published its results from early phase 2 trials on 500 subjects in the same issue of The Lancet. Both the Oxford and Chinese labs are developing a recombinant vaccine in which the genetic sequence for the CoV-2 spike protein is engineered to be expressed as part of a crippled adenovirus genome. The adenovirus will infect human cells, but not replicate or cause disease. 

The third vaccine is being developed by the pharma giant Pfizer and the German biotech company, BioNTech. This is a highly novel RNA vaccine where just a simple genetic sequence from the CoV-2 virus is used to immunize patients. No virus is used at all, just some of the virus genetic material. They recently reported in a pre-print paper that has not yet been peer-reviewed, similarly encouraging results from a combination phase 1/2 trial on 60 subjects.

The results of the three studies were very similar. The vaccines were all safe and there were no serious side effects. The only problems were an occasional temporary fatigue, sore arm or headache, which were treated with Tylenol. These effects are much more pleasant than coming down with COVID-19.

Importantly, all three vaccines were shown to stimulate both arms of the adaptive immune response, which is a crucial factor for a successful vaccine. The first arm is the B cell, or bone marrow-derived lymphocyte response. B cells produce antibodies that neutralize the virus, but they fade away after the infection is cleared, not providing long term immunity. The second arm is the thymus-derived lymphocyte, or T cell, response. Activating a T cell response is particularly important for a successful vaccine because it is what oversees the whole immune response to a pathogen and, more importantly, produces long lived memory T cells that impart a long term sentry function to the pathogen, which is what “immunity” is. Memory cells are the basis for long-lived vaccine protection. A successful vaccination will produce memory cells that will sound an alarm if you are later exposed to the pathogen. This alarm rapidly mobilizes your immune system to make a very robust defense that prevents the infection from developing. Therefore, it is very encouraging that the experimental vaccines activated T cell responses.

The Oxford vaccine stimulated T cell immune responses within 14 days and antibody responses in 28 days. Both responses were also stimulated within 28 days in the Chinese study. The Oxford and Chinese studies showed that 85-90% of vaccinated subjects developed antibodies that neutralized the virus and that response was sustained up to 56 days, which is how long the longest study followed the recipients. T cell responses were also seen in 90-100% of the vaccine recipients. The Chinese study further reported that people over 55 developed weaker responses than younger subjects, which was expected. The Oxford study only enrolled volunteers under 55 years. While employing a much smaller sample size, the German study had results similar to the Oxford and Chinese studies.

It must be cautioned that these very encouraging phase 1 and 2 studies did not test whether the immune response could actually protect people from the virus. In other words, they did not test whether the vaccines produced memory cells that could confer long-term immunity. This will be tested in the large phase 3 trials that will begin as early as the end of July. These will be massive studies involving tens-of-thousands volunteers. Phase 3 studies also will take longer since they require the subjects to be naturally exposed to the virus and develop COVID-19. After a period of time, the number of unvaccinated control subjects who develop the disease will be compared to the COVID-19 incidence in vaccinated subjects in order to learn if, and to what extent, the vaccine can protect against the virus. These results should be forthcoming in a few months. Phase 3 trials also will pay attention to vaccine safety in a much larger cohort of subjects than tested in the earlier trials.

If the phase 3 studies show that the vaccines can protect people against future infection with the virus and are safe, then they will be approved. In anticipation of this, some large pharma companies, such as AstraZeneca and Pfizer are already producing the, still experimental, vaccines. This means that if they prove effective, there will be a stockpile of vaccine that can be immediately dispensed around the world. The companies also have pledged to provide the vaccines at cost.

Just a few weeks ago, worry was that the virus seemed to be petering out and that it would be hard to find sufficient numbers of volunteers to undertake large phase 3 studies. However, as the virus is rebounding in most US States and is gathering steam elsewhere in the world, that does not seem to be a problem anymore. Just one week after the National Institutes of Health launched a clinical trial network for vaccines and other prevention tools to fight the pandemic, they announced that 107,000 Americans have already volunteered for vax studies. It is estimated that 120,000 volunteers are needed to adequately test the four lead vaccine candidates under development in the US (assuming 30,000 subjects are needed to test each vaccine). So the high enrollment is a good sign that the vax studies will not be hampered by low enrollment.

Stay tuned. We will see.