Vaccine preparation and clinical trials

In my last blog, I mentioned that I will present various aspects of clinical trails in the preparation of vaccines. So, here it is.

Peter Piot who played a key role in the HIV epidemic and then the Ebola crisis has made this statement. “Let us be clear: without a corona vaccine we will never be able to live normally again. The only real exit strategy from this crisis is a vaccine that can be rolled out worldwide.” If a vaccine is so important, then you may be interested in knowing as well as find it useful to know how we reached this stage where we have a number of vaccines available.

Research centres and companies throughout the world worked at breakneck speed to develop a vaccine for this disease. There are certain biases that come in such haste. If the disease attacked only the developing world, there normally would not have been such a big hurry. Since this has hit the developed countries far out of proportion to the developing world, there is a certain urgency in this process. In this blog, I would like to explain the steps or phases involved in developing and making a vaccine available for wider use public use.

Phases of vaccine research

There are at least six steps in carrying out research on developing a vaccine. I’ll take you through these six steps briefly for your understanding.

Step 1. Identifying the antigen or the substance that would be administered to an individual that would produce the desired response of generating the antibodies to these antigens. In some vaccines, live but half-killed or attenuated organisms are used as the antigen. The Covishield or the Oxford vaccine belongs to this category, using chimpanzee adenoviruses. The Covaxin of Bharat Biotech uses inactivated or killed SARS CoV2 virus. In other vaccines such as the Pfizer vaccine, parts of the organism are used as the antigen using a technology called mRNA. This explains the three broad types of vaccines available today.

Step 2. In this step, the selected antigen is tried out in test tubes in laboratories and then on animals. Effectiveness and safety are looked at this stage.

Step3. – Phase 1 clinical trials. In this phase what has been developed in the laboratory is now tested on actual human volunteers. Again, effectiveness and safety in the humans are looked at this stage. Very few individuals are used at this stage.

Step 4 – Phase 2 clinical trials. In this phase, a small number of volunteers get the vaccine and then they are challenged with the disease. The immunised volunteers actually receive the disease germs and then they determine whether the vaccine actually prevents the disease or not. Safety is an important consideration here.

The difficulty with COVID-19 is that there are no one hundred percent effective medicines for the disease. What if the vaccine fails and the volunteer gets the disease and even dies? These considerations have always slowed the pace at which these early phases have gone through.

Step 5. – Phase 3 clinical trials. In this phase, the vaccine is made available to a larger population but still under research supervision and based on the written consent given by those in the trial. Over forty years ago, I had the privilege of being an administrator for a major research on injectable polio vaccine, a killed polio vaccine, under the Head of Virology Department, Dr Jacob T John. At the end of phase 3 trials, we were able to prove that the injectable polio vaccine was effective and safe in a rural Tamilnadu population in India.

The issue with COVID-19 vaccines has been that different vaccines had their phase 3 trials completed at different points in time. In India this has become an issue, that the Covaxin of Bharat Biotech has not completed the phase 3 trial and it has been given emergency use license. This is why, those who receive this vaccine have to sign a consent form agreeing to be part of the phase 3 trails, till the number to be involved in the phase 3 is completed. Many experts are questioning the reason for this hurry without phase 3 trials. Even a case has been initiated in the Supreme Court.

Step 6. – Phase 4 clinical trials. In this phase, it is carried out as a marketing exercise. It is freely used in the ongoing health care delivery system. The administering of Covishield comes under phase 4 as they have completed the phase 3 trials. Generally, after phase 3 trials, it is expected that the results of the trial must be published in a reputed medical journal refereed and reviewed by subject experts before phase 4 is started. In India both Covishield and Covaxin have not published their Indian experience. This is another drawback of the Indian vaccination programme.

In my experience mentioned earlier, after the phase 3 trials with injectable polio, it went on to phase 4. Phase 3 was in a small geographic area of one development block or county. In phase 4 it covered the whole district consisting of nearly forty such blocks or units. I was not directly responsible at this stage, but I was involved with the team. There were certain design issues which resulted in not showing the same level of effectiveness of the injectable vaccine seen in phase 3. Therefore, this injectable vaccine was rejected then. Only after repeated difficulties faced with the oral polio programme using live attenuated polio virus drops was the injectable vaccine brought back in the final assault on polio.

Before I go further on vaccine trials, I must highlight handling some of the ethical issues involved in such type of research. The first is recruiting volunteers for such trials. There are clear international guidelines that state how volunteers could be brought into the research and their rights and protection.

In such research, the participants have the right to comply or not comply with the research protocols at any stage. Always a signed written consent statement is obtained from anyone who participates in such research.

One last ethical decision concern is the need to have a comparable group. One group will have the vaccine and the other may not get anything or they get what is called a placebo. In this case it being water or saline which is an inert or inactive substance that is harmless. Again, there are strict guidelines followed by research institutions when control groups are used.

Now you can understand the complexity of developing a new vaccine for COVID-19. There are strict protocols to be followed, although there are temptations to shortcut the steps because of the suddenness of the disease and the rapidity of its spread. By the time a vaccine goes through these phases, it was predicted that it could be a year or more before it was available for immunisation. But then the vaccines arrived much earlier than expected.

There is then always the question, whether there were short cuts in this vaccine race. Very clearly the phase 3 trials have not been completed in all vaccines. Not all vaccine trials have been published in journals. The manner in which reactions to the vaccines have been handled have also raised questions and doubts. There have been a number of deaths associated with the vaccines. It is not clear that these have been reviewed by competent neutral experts to determine if there is any relationship with the vaccines.

I am going back to the statement made Dr Peter Piot indicating the need for a vaccine before we can go back to the type of normal living of the pre COVID-19 era. Even with a number of vaccines available today, there are certain issues associated with it discussed below.

The companies which have invested in vaccine research have the primary purpose of making profits. The initial indications are that they are not going to be cheap. Richer countries may be able to afford them. Even there the poor in those countries may not get it easily unless the governments intervene in an equitable manner. WHO has called this vaccine nationalism.

The next issue to be addressed is to produce millions or even billions of vaccines if it has to be effective. Whether these large quantities could be produced so quickly is one important consideration. The price fixed by the companies would determine how freely these large quantities are available for those who need.

We are witnessing around this time a community backlash against any vaccines to be given. The anti-vaccine lobby is very powerful in some of the countries. The US which had successfully controlled measles as a disease has seen it come back in epidemics, because parents have refused to give the measles vaccines to their children. Similar objections to this vaccine could also create problems in controlling the disease. A large number of potential recipients are refusing to take the vaccine in different countries.

Only now after the initial round of experience with the different vaccines, for those whom it is contraindicated is beginning to emerge. In my next blog, I’ll share a list of those who should not take this vaccine.

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Published by rajaratnamabel

Having completed my undergraduate medical education from Christian Medical College, Vellore, India. Then I had the privilege of completing my Master of Public Health from the Johns Hopkins University, Baltimore, USA. I could also complete my PhD in Chennai, India. Based on my extensive work in nutrition backed by a number of scientific publication, I also received the Fellowship of the International College of Nutrition (FICN). I retired from active service in 2005. Since then God enabled me to be a Consultant Public Health Physician, at the SUHAM Trust of the DHAN Foundation in Madurai. I am involved in providing community based health care support to a large number Self Help Groups in 14 Indian states.

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