Arrival of the Vaccine: Mission Accomplished?

The year 2021 is slated to be the year of minimizing the impact of COVID 19, which played havoc with the lives of close to a billion people worldwide. There have been 94.5 million cases diagnosed with 2 .02 million deaths. Fortunately, the mortality in our part of the world has been consistently lower 1.2 vs 2.2% (global). Recent, months have shown a decline in the numbers but fresh waves and outbreaks with new mutants always pose a threat like in England and USA.

How to increase the immunity to cut off the morbidity and mortality to negligible figures while the virus is still there. Diligent scientific work done in the year 2020 towards developing a vaccine, has paid dividends. In this short and a record period, we have the availability of several vaccines based upon a variety of principles. Every country has its approval procedure on which depends the vaccine use.

The results of the Pfizer and Biontech’s, mRNA-based COVID-19 vaccine was published and they submitted its data to US FDA in December 2020. It met the study’s primary efficacy endpoints with an excellent data in the participants without prior SARS-CoV-2 infection (first primary objective) and also in participants with and without prior SARS-CoV-2 infection (second primary objective). The observed efficacy in adults over 65 years of age was over 94%. It was approved in USA and Canada and several European countries. The immunization has started although there is delay in shipments in several sectors because of limited production and also very fastidious requirements of temperatures of minus 70 degrees needed for transport and storage. The safety issue however, has of late come under a cloud with 29 deaths been reported in Norway out of 42,000 administered. All of them have been elderly people (>75 years) with several associated illnesses. Some countries like Australia which were to start their program have put it on hold pending enquiries about the deaths.

This m RNA based vaccine from USA and Europe, is not likely to come to Indian markets in the near future because of its cost and the tough storage requirements.

Adeno Vector Based Vaccines:

The Russian vaccine Sputnik V: The first heterologous COVID-19 vaccine consisting of two components has been used extensively in Russia with a good reported safety and efficacy. However, the vaccine was released after only Phase I/II studies in a very small number of volunteers and the protocols were not published, this drew criticism from the scientific fraternity. On the basis of this small data, it was given to more than 40,000 people in Russia and Belarus. The vaccine had received a registration certificate from the Russian Ministry of Health under emergency rules adopted during the COVID-19 pandemic. Other countries to get a nod for its use are: Serbia, Argentina, Bolivia, Algeria, and Palestine. As per the recent reports from the manufacturer the vaccine has been administered in more than a million subjects in several countries without any safety concerns.

Sputnik vaccine currently in collaboration with Dr Reddy’s lab, is in a placebo-controlled Phase III (1000 volunteers’ trial) in India. The completed Phase I and II data has been approved by the DCGI and Phase III was started on 17th of January 2021. The 6 months results of antibody response are likely to be available by mid-2021 before the final decision of a general approval for its use can be expected.

Oxford Astra-Zeneca Vaccine:

The vaccine is the chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19). This is the only vaccine available in India currently which has completed the phase III and shown an acceptable safety profile, along with a homologous boosting increased antibody response in a large placebo-controlled trial of 23,848 subjects in England and Brazil. The overall vaccine efficacy was 70·4%, seen within 21 days after the first dose. The time interval between 2 recommended shots was 4 to 12 weeks. This data was published recently in December 2020, leading to its approval in England. The Drug Controller General of India (DCGI) gave the approval for use in India on 2nd January this year. Longer term data will come by the end of the year making things clearer.

The Serum Institute of India, a Pune based company, the largest manufacturers of vaccines in India, has a collaboration with Astra Zeneca for bulk manufacture and had already a stockpile of 50 million vaccines (Covishield) which have been sent to all the Indian states under Government of India directives. The immunization program using this vaccine started on 16th January under the supervision of the PM, Mr Narendra Modi. The distribution is being done in a phased manner giving priority to frontline health workers.  The vaccine does not have very fastidious requirements for storing and transporting beyond what is available with us in the country.

COVAXIN:

This adenovirus-based vaccine manufactured by the Bharat Biotech, a Hyderabad based leading vaccines & bio-therapeutics manufacturers in India (with the experience of Rotavirus, Hepatitis-B, Typhoid, Polio etc), after completing the phase I and II are in the phase III trial of a planned 26,000 volunteers. The results of Phase III will take at least 3 more months. This vaccine has also been approved for a roll out in an accelerated approval in a “clinical trial mode” along with the Covishield vaccine from AstraZeneca.

As per the Union government’s directive all the states/priority-group beneficiaries will have no choice over whether they receive Bharat Biotech’s Covaxin or the Oxford/AstraZeneca-developed Covishield . More clarity is needed regarding the meaning of the “Clinical Trial mode” in absence of a control arm. The immunogenicity and safety data from phase I/II clinical trials is not enough for approving the clinical use of a vaccine. All the subjects being given this vaccine have to give a written consent for immunization, since the vaccine at present is in a trial mode.

If regulatory authorities allow vaccines with inadequate or evolving data to be brought into field, the subjects need to be given a choice to select or reject the vaccine as per the standard guidelines of Ethics governing Clinical trials. Subjects being offered COVAXIN need to have a proper consenting process if they are entering the “clinical trial mode” of use till Phase III results regarding safety and efficacy are published.

Cadila Vaccine:

Zydus Cadila of India is working with 2 COVID vaccines, one using DNA and the other using Replicating Viral Vector. The company has the past experience of making a vaccine against H1N1- Vaxi Flu S in the shortest possible time.

Their novel DNA based vaccine will complete the Phase III studies by the middle of March 2021 before applying to the Government for an approval. It is quite appropriate for the company to wait till the phase 3 results are available.

Research and Development in Progress:

In addition to the 3 vaccines enumerated above there are at least 2 more vaccines in various stages of development in the country.

  1. Biological E (BE), based in Hyderabad, is currently working on a protein-based vaccine. The BE vaccine is being developed in collaboration with the Baylor College of Medicine, US.

The company is, however, conducting its human trials in India with Phase 1 currently underway. According to the health ministry estimates, BE’s Phase II trials may begin in March 2021.

BE announced that it has secured $5 million funding from the Coalition for Epidemic Preparedness Innovations (CEPI) for scaling up manufacturing of its protein subunit Covid-19 vaccine in December 2020.

  • Gennova’s vaccine is India’s first mRNA Covid-19 vaccine that can be stored at 2-8°C. Pune-based Gennova Biopharmaceuticals has also entered the human trials.

The Indian drug regulators have approved the Phase 1 trials of this vaccine in India and Phase 2 trials should begin in March 2021.

mRNA based Pfizer vaccine which requires sub-zero temperature is being seen as the biggest challenge in India. Gennova’s vaccine, therefore, can come in handy for our country since the requirements for storage are much easier.

Take home message and how to choose, given a choice?

Choice of the vaccine has to be dependent on the data it has on an adequate number of volunteers. The studies need to have a control or a placebo arm. Protocols of the studies should be in public domain and in peer reviewed scientific journals. The phase 3 results should have observation periods of adequate length and need to be reviewed by experts in the field. Trial outcomes need a Scientific verification and should not be influenced by political pressure and deadlines. The ultimate aim is to make the infection as innocuous as possible. Resumption of normalcy of health with negligible morbidity and mortality of COVID 19 and revival of economic slump depends on the long-term efficacy of the vaccines. The hygienic measures learnt during the year 2020 need to be continued indefinitely and should become a part of the life.