Prospects of Vaccine against COVID-19.

COVID-19 was first detected in China toward the end of 2019 and spread to the various parts of the globe over the next few days. The World Health Organization (WHO) declared it a pandemic on March 11, 2020.[1] The world has seen a pandemic of this scale for the first time in around a 100 years. Within 9 months of its detection, the virus has spread across to almost all countries and affected around 3.5 crore people. In India, more than 70 lakh people have already been infected till now.[23]

Various preventive measures have been proposed by the WHO and health ministries of different countries such as the use of masks, social distancing, hand hygiene, and respiratory etiquettes.[4] This has led to a lot of changes in our day-to-day lifestyle. Most of the countries have also imposed nationwide lockdowns of varying lengths and intensity, in an attempt to break the chain of transmission.[5] The success of these nationwide lockdowns in reducing the number of cases is debatable; however, they have been able to delay the peak of the epidemic as predicted by few modeling exercises. With this delay, countries, especially the developing ones like India, got time to gear up and prepare themselves to handle a surge in the number of COVID-19 cases.[6]

In several European nations, after the initial decline and subsequent relaxation of the lockdowns, the number of COVID-19 cases has again started to escalate. It is predicted that the disease is here to stay and probably may even become endemic.[7] However, the conundrum still remains – when will the pandemic subside? To this, it has been argued that the end line may be different for different countries and will be affected by many factors, the important one being the availability of an effective and safe vaccine against COVID-19. Hence, the urgent need of an effective vaccine to check the spread of the disease.[89]

Efforts are being made globally to develop an effective and safe vaccine against COVID-19 to tackle the pandemic. As on September 3, 2020, there were 320 vaccine candidates globally in different phases of clinical trials, out of them 6 are in Phase III clinical trial (as on September 17, 2020), as indicated in Table 1.[10] Of the mentioned candidate vaccines, clinical trials for three candidate vaccines have also been started in India.[101112]

Table 1

COVID-19 vaccines in clinical development

Candidate	Lead partners	Vaccine characteristics	Start of Phase-I trial	Current stage
AZD1222	AstraZeneca/Oxford University	ChAdOx1vector that expresses S protein	April 23, 2020	Phase II/III (NCT04516746)
Gam-COVID-Vac	Gamaleya Research Institute	Recombinant adenovirus vector based on the human adenovirus type 5, 26, containing S protein	June 18, 2020	Phase III (NCT04530396) Conditional registration in Russia
ZyCoV-D	Zydus Cadila	DNA vaccine	July 15, 2020	Phase I/II (CTRI/2020/07/026352)
mRNA-1273	Moderna Therapeutics/NIAID	LNP-encapsulated mRNA that encodes S protein	March 16, 2020	Phase III (NCT04704427)
mRNA-BNT162	Pfizer/BioNTech	LNP-encapsulated mRNA that encodes stabilized S antigen	April 29, 2020	Phase II/III (NCT04368728)
Inactivated SARS-CoV-2 vaccine	Wuhan Institute of Biological Products/Sinopharm	Inactivated novel coronavirus pneumonia vaccine (Vero cells)	April 11, 2020	Phase III (ChiCTR2000034780)
Adsorbed COVID-19 (inactivated vaccine)	Sinovac Biotech	SARS-CoV-2 inactivated vaccine	April 16, 2020	Phase III (NCT04456595)
BBV 152	Bharat Biotech	Whole-virion inactivated	July 14, 2020	Phase I/II (CTRI/2020/07/026300)

*Adopted from Le et al.

The available candidate vaccines against COVID-19 vary from the traditional whole pathogen vaccines to new-generation vaccines. The traditional whole pathogen vaccines are live attenuated vaccine (LAV) having live pathogen with reduced virulence and killed vaccines contain pathogens inactivated by heat or virucidal chemicals. While LAVs may also introduce, among recipient, mild infection which most of the time resembles natural infection, it also leads to the development of a stronger and long-lasting immune response. The LAV do have some safety concern, but they also have good reactogenicity as compared to new generation recombinant vaccines.[1314]

The killed/inactivated vaccines, on the other hand, are relatively safer as they do not contain live pathogens, but they have lower immunogenicity and most of the times require multiple doses to establish a strong immunological memory. The new generation vaccines, including recombinant and vector base vaccine, uses the specific antigen or antigens from pathogens instead of whole pathogens and thus provide better safety profile. However, it takes a longer time to properly understand the pathogen and to initiate the development of recombinant/vector base vaccines.[1314]

Vaccines have their own safety concerns, especially the LAVs. Adverse events following immunization (AEFI) need to be evaluated in clinical trials. Available evidence on some of the candidate vaccines have demonstrated that the immediate AEFI are limited to mild to moderate self-limiting conditions such as fever, pain at site, myalgia, fatigue etc.; however, long-term AEFI is yet to be evaluated.[1516171819] With respect to coronaviruses, Antibody-Dependant Enhancement (ADE) of disease is of special importance as has been argued previously for animal coronaviruses, SARS-CoV and Mers-Co-V. This has also been observed in other viruses such as HIV and dengue.[1420] However, currently, there is no evidence to suggest the possible role of ADE in exacerbating the disease severity in COVID-19.[21]

The governments and vaccine developers are trying their best to introduce the vaccines for use by general public by the end of 2020 or may be even earlier. Vaccine development critically is a long process, and sometime, it takes several years to develop a vaccine. However, in COVID-19 case, since there is a global crises, everybody is hoping for an early vaccine. However, it will be difficult to prove the long-term safety and efficacy in case a vaccine gets approved within this timeline and long term side effects may be missed in expedited and short lasting trials. For example Moderna mRNA-1273, developed by a US based firm entered the clinical trial cases just after 66 days of identification of SARS-CoV-2 genetic sequencing which showcased potential for nucleotide based vaccine. Along with Moderna, another mRNA based candidate vaccine (mRNA-BNT162) being developed by Pfizer is expected to have the vaccine efficacy results by November. The results of early trials are promising for both the candidate vaccines so far.

Russia has already approved its candidate vaccine “Sputnik V” for civil use based on early reports of safety from its Phase I/II trails and has released the first batch for the same. The vaccine is based on human adenovirus vectors.[22] However, apart from the completion of phase III trial, one more concern with the vaccine will remain that many people would already be immune to human adenoviruses, and the existing immune response may pose a hindrance in developing immunity against SARS-CoV-2. In view of this, it becomes necessary for currently ongoing expedited trials to set up a system to monitor the vaccines once it is approved for being administered to general public.[8]

COVID-19 VACCINES IN INDIA

Covaxin developed by Hyderabad-based Bharat Biotech and ZyCoV-D developed by Zydus Cadila has been approved for Phase I and Phase II trials. Covaxin has subsequently completed Phase I trials and is undergoing Phase II trial at 12 different sites[11]

Covishield vaccine has been developed by Serum Institute of India in agreement with a British Firm – AstraZeneca. The vaccine has subsequently completed Phase II trial and Phase III trial is going on at 17 different sites[11]

Novavax: The vaccine candidate being developed by an American Company which is likely to begin trials in late October. The vaccine is currently in Phase II trial in South Africa. In India, Novavax has entered into an agreement with Serum Institute of India. ICMR and Serum Institute of India are partnering in clinical development of Glycol protein subunit nanoparticle adjuvant vaccine developed by Novavax from USA. The trial is led by National AIDS Research Institute, Pune[12]

mRNA-1273 US based Moderna vaccine is also likely to start Phase III trials in India in near future may be by December 2020[12]

Sputnik V: After Russia's approval of its candidate vaccine Sputnik V, Hyderabad based Dr. Reddy's Laboratories has made an agreement to procure the vaccine and conduct the Phase III trials in India possibly from October 2020, following which it will initiate large scale production of the vaccine.[22]

Intranasal Single dose Vaccine:

Bharat Biotech has entered in an agreement with Washington University School of Medicine for developing and large scale manufacturing of a novel chimp-adenovirus intranasal vaccine for COVID-19. While the Phase I trial of the vaccine will be conducted in St Louis University, Bharat Biotech is slated to pursue further stages of clinical trial in India[23]

Serum Institute of India has started manufacturing COVID-19 candidate LAV (CDX-005) developed by Codagenix Inc, US Biotech firm. The vaccine has shown encouraging safety and efficacy potential and Phase I clinical trial will probably be initiated in the UK by the end of 2020.[24]

Similar attempts are also being made in England and China as there is a global appetite for a successful vaccine. Governments, vaccine developers, and other international funding agencies have already started investing for large scale manufacturing of vaccines but at the risk of subsequent vaccine failure in clinical trials. Even after successful clinical trials, when the vaccines are ready to be launched, there will be certain issues such as financing, procurement, equitable vaccine distribution and storage of vaccines, which will need considerations while planning. Finally, monitoring of vaccinated individuals may be a challenge in the absence of a robust monitoring mechanism by sponsors of clinical trials.[25]

The antigenic mutations have impacted the vaccine development for a number of diseases such as HIV, malaria, and influenza. SARS-CoV-2 like other RNA viruses is prone to mutations. Cumulative effect of these mutations may enable the virus to escape the immunity developed after vaccination and impact the efficacy and longevity of immunity provided by these vaccines. As most of the vaccines target the spike protein, one mutation in spike protein 'D614G' may be important in this aspect. Monitoring such mutations, especially on vaccine target sites will be important for vaccine development in future. According to a report, the nucleotides of SARS-CoV-2 show about 99% similarity across different lineages, thus encouraging the efforts of vaccine development.[1426]

After the approval of a vaccine against COVID-19, the countries may face a lag or short supply of vaccine doses. Governments may have to adopt a phased and targeted approach to handle the situation carefully and smartly. For this, they may prioritize the population groups who will get the vaccine in the initial phase. Such population groups should include those who are at high risk of contracting the infection while discharging their professional duties such as health care workers, police personnel, persons in other essential occupations where duties cannot be performed remotely or those at high risk of suffering from severe form of the disease and subsequent mortality such as the elderly and those with other comorbidities. Further, there should be enough flexibility in the national guidelines to allow vaccine administration as per local epidemiology and needs.[27]

The safe transportation and storage of vaccines are another important area to be strengthened. A report by Inclen Trust exposes the suboptimal state of cold chain infrastructure and exposure of vaccines to wide temperature excursions during storage and transportation in India.[28] Such issues may have implication with the Government looking to procure large doses of vaccines. Assessment of the available infrastructure and re-purposing of existing infrastructure seems to be a solution to quickly prepare ourselves for handling these large doses of vaccine. Alongside, a robust monitoring mechanism to ensure vaccine integrity will also be needed.

India is a party to the COVID-19 Vaccine Global Access (Covax) agreement, an initiative by Global Alliance for Vaccine and Immunization in collaboration with WHO and Coalition of Epidemic Preparedness (CEPI). Covax is a financing instrument to incentivise vaccine manufacturers to produce sufficient quantities of potential coronavirus vaccines and ensure access for developing countries at affordable costs. However, given the huge demand of vaccine, it will still have financial implications on the government to procure the doses required in addition to the 20% vaccines which they will get through Covax.[29]

National Expert Group on Vaccine Administration for COVID-19, deliberated on a digital infrastructure for inventory management of COVID-19 vaccine which would also enable tracking of vaccination process. Financing options, central procurement mechanism through Ministry of Health and Family Welfare, available infrastructure for delivery and roll out of for vaccines, prioritization of population groups, and strategy for equitable and transparent distribution of the vaccine along with Strategies for community awareness and involvement, ensuring safety and surveillance have also been discussed at the national level.[30] Following this the Government has already initiated arrangements to utilize approximately 500 million doses by July 2021 and have directed to the states to make such plans by October 15.[31]

The Drugs Controller General of India (DCGI) has issued a new set of guidelines, focusing on safety, immunogenicity, and efficacy parameters for pharma giants who are developing COVID-19 vaccines. The DCGI has said that a COVID-19 vaccine candidate should have at least 50 percent of efficacy in the Phase-III clinical trial for it to be widely deployed and adequate data informing the potential risk of vaccine-associated Enhanced Respiratory Disease needs to be generated.[31]

In spite of the challenges, there is an urgent need of a suitable COVID-19 vaccine in India and globally. For this, we have to plan in the domain of production and financing, safety and efficacy of vaccine, availability, equitable distribution, and accountability of the vaccine in order to ensure the process of COVID-19 vaccine adoption to be easier and acceptable to all.[32] During his address at the 75th national UN assembly in September 2020, the UN Secretary-General António Guterres, urged countries to work together to facilitate access to an affordable vaccine for everyone, everywhere.[33]

In order to control the pandemic, the imminent need of a safe, effective and acceptable vaccine is evident. In spite of the challenges, the possibility of a vaccine getting approval for public use in India seems to be likely in early/mid 2021, if the trial results are favorable. However, several issues, as highlighted above, surrounding the procurement and distribution of vaccines will have to be addressed, to ensure a hassle-free vaccination drive. The time till vaccine approval should be gainfully utilized to undertake preparatory steps for the future vaccination strategy, covering all the aspects of an effective and safe vaccination against COVID-19. Only time will tell how well prepared our system is to handle these challenges.