The world is in the midst of a COVID-19 pandemic. The scientific fraternity and experts from various domain are working together to tackle this serious public health problem. They are advising on critical interventions, distributing vital medical supplies to those in needs— they are racing to develop and deploy safe and effective vaccines.
Vaccines save millions of lives each year. Vaccines work by training and preparing the body’s natural defenses — the immune system— to recognize and fight off the viruses and bacteria they target. If the body is exposed to those disease-causing germs later, the body is immediately ready to destroy them, preventing illness.
There are currently more than 50 COVID-19 vaccine candidates in trials.
Several different types of potential vaccines for COVID-19 are in development, including:
- Inactivated or weakened virus vaccines, which use a form of the virus that has been inactivated or weakened so it doesn’t cause disease, but still generates an immune response.
- Protein-based vaccines, which use harmless fragments of proteins or protein shells that mimic the COVID-19 virus to safely generate an immune response.
- Viral vector vaccines, which use a virus that has been genetically engineered so that it can’t cause disease, but produces coronavirus proteins to safely, generate an immune response.
- RNA and DNA vaccines, a cutting-edge approach that uses genetically engineered RNA or DNA to generate a protein that itself safely prompts an immune response.
Following vaccine candidates are in advanced stage of development or recently approved:
|1||BNT162b2||mRNA||Pfizer/BionTech||Approved in UK/ US/ Canada|
|2||mRNA 1273||mRNA||Moderna||Phase III/Applied in EU, Approved in US|
|3||AZD1222||Adenovirus vector||AZ/Oxford/Serum||Phase III/Rolling review|
|4||Covaxin||Inactivated virus||Bharat Biotech||Phase III|
|5||Zycovid D||DNA vaccine||Zydus Cadila||Phase II|
|6||JNJ 78436735||Viral vector||J & J||Phase III/Applied in Europe|
|7||Sputnik V||Viral vector||Moscow/DRL||Phase III/Approved in Russia.|
|8||NVX-CoV2373||Nanoparticle vaccine||Novavax||Phase III|
|9||INO-4899||DNA vaccine||Inovio Pharma||Phase II/III|
Two intranasal vaccines by Altimmune are under early stage of development.
Developing safe controlled human infection models (CHIMs) for human trials could take 1-2 years. A sponsor would need to provide data from placebo-controlled trials indicating their vaccine is at least 50% effective against COVID-19 in order to be authorized for use, according to FDA guidance issued and effective 30 June, while the European Union’s chief drug regulator has suggested the EU would approve a vaccine with less than 50% efficacy. Additional FDA guidance on COVID-19 vaccine Emergency Use Authorization (EUAs) was released on 06 October. The guidance calls for interim analysis based on a clinical endpoint in a Phase 3 trial of at least 2 months in over 3,000 participants, as well as relevant safety and efficacy data from Phase 1 and Phase 2 trials.
BNT 162 b2: BNT162b2 (Pfizer’s COVID-19 mRNA vaccine) is a nucleoside-modified RNA, formulated in lipid nanoparticles. The pivotal study of this vaccine was conducted in more than 43,000 human subjects. In this randomized, placebo controlled study 21,720 subjects above 16 years of age received vaccine (BNT162b2) and 21,728 received placebo (dummy injection). The vaccine was administered intramuscularly in two dosage of 30mcg each at an interval of 21 days.
A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. Primary efficacy demonstrates the efficacy beginning 28 days after the first dose; 162 confirmed cases were found in placebo group versus 8 in the vaccine group. Efficacy was consistent across age, gender, race and ethnicity. Efficacy in adults over 65 years was over 94%. There were no major safety issues. 3.8% subjects experienced severe fatigue and 2% headache. There are two reports of anaphylactoid reactions (allergic) to this vaccine after mass immunization in UK, which occurred in individuals with a history of severe allergic reactions. The government agencies have issues recommendations that people with allergies to any of the ingredients of the vaccines should not receive the vaccine.
mRNA-1273: Moderna’smRNA-1273 was developed based on prior studies of related coronaviruses. A Phase III trial (COVE trial) of 30,000 subjects at high risk for Covid-19 infection is underway. Participants will receive a 100 mcg dose of mRNA-1273 or placebo and then to be followed for up to 2 years. An interim analysis of 95 participants in Phase III was released by Moderna on 16 Nov, 2020. The non-peer reviewed data indicate mRNA-1273 has an efficacy of 94.5%. There were no severe cases of Covid-19 in the vaccinated group compared with 11 cases in the placebo group. Overall, the company said the vaccine was well tolerated with no significant safety issues. Moderna received Emergency Use Authorization (EUA) in USA for mRNA-1273 on 17 Dec, 2020. Moderna requested conditioned marketing authorization from European regulatory (EMA) for mRNA-1273 on 1 Dec, 2020. European regulatory is reviewing the data and an extraordinary meeting is scheduled on 6 January 2021 to take the final decision on its approval. This vaccine is to be injected intramuscularly in two doses at an interval of 28 days.
AZD1222 (COVISHIELD): Astra Zeneca and Oxford Vaccine Group at the University of Oxford are developing AZD1222, a chimpanzee adenovirus vaccine. In India, the vaccine is being jointly developed by the Serum Institute of India and Astra Zeneca. A phase III clinical trial is underway and has enrolled more than 40,000 human subjects. A Phase II/III trial conducted by the University of Oxford of up to 12,290 participants is active and currently recruiting. The interim data from a Phase III trial in the UK, Brazil and South Africa published in the Lancet indicates the vaccine has an overall efficacy of 70% with vaccine efficacy at 62.1% in a group of participants receiving two standard doses and 90% in a group receiving one half the dose followed by one standard dose. A report of Phase II data published in The Lancet showed the vaccine candidate has similar immune response in all age groups but appears to be better tolerated in older age.
Preliminary results published in The Lancet showed the vaccine has acceptable safety profile with most subject demonstrating immune response after first dose and all patients showing immune response after two doses. There has been one death in a Phase III trial in Brazil, which was confirmed by Brazilian Health Agency (ANVISA).
Phase III clinical trials are being conducted in USA and India, but were put on hold following a serious adverse event. Trials have since resumed. Serum Institute of India had applied for Emergency Use Authorization (EUA) in the country from Drug Controller General of India (DCGI). However, DCGI has asked for more data on safety and efficacy of this vaccine. European authorities have started a rolling review of AZD1222 to reduce the time of approval. In Australia, TGA granted provisional determination, the first step in the process of approval. MHRA in UK has also started accelerated review of this vaccine. AZD1222 is to be given two doses at 28 days interval by intramuscular injection.
Covaxin: India’s indigenous Covid-19 vaccine by Bharat Biotech is developed in collaboration with the Indian Council of Medical Research (ICMR) and National Institute of Virology (NIV). After successful completion of the interim analysis from Phase I and II clinical trials Covaxin, Bharat Biotech received DCGI approval for Phase III trial in 26,000 subjects in over 25 centers across India. Bharat Biotech had applied for approval but DCGI asked for more data on safety and efficacy. The vaccine is to given intramuscularly in two doses at 28 days interval.
Zycovid-D: India’s Zydus Cadila is researching Zycovid-D, a plasmid DNA vaccine candidate for Covid-19 that targets the viral entry membrane protein of the virus. The company has launched an adaptive Phase I/II dose escalation trial and plans to enroll about 1000 healthy volunteers. On 5 Aug, Zydus announced the phase I was complete and vaccine was entering Phase 2 trials. Zycovid-D is injected intradermally in three doses at 0, 28 and 56 days.
JNJ 78436735: Janssen, a pharmaceutical company owned by Johnson & Johnson is developing JNJ 78436735, using their viral vector technology. The Phase III ENSEMBLE trial will enroll up to 60,000 participants in US and across the globe. A Phase III two dose test of this vaccine (ENSEMBLE 2) is being evaluated in up to 30,000 subjects and will run alongside ENSEMBLE. ENSEMBLE trial was on hold following an adverse event in a subject but resumed after data review by expert committee. Additionally, a randomized, placebo controlled, double blind, Phase I/II study is ongoing in 1045 healthy volunteers 18-55 years of age and adults 65 years and older. Study sites are in US and Belgium. Australia has given provisional determination to this vaccine. This vaccine is also undergoing rolling review by European authorities. Safety and efficacy outcome of JNJ 78436735 in animal studies are very encouraging. Vaccine is given intramuscularly in two doses on first day followed by single dose on 56th day.
Sputnik-V: The Gamaleya Research Institute in Russia and Health Ministry are evaluating their viral vector vaccine Sputnik-V in a Phase III trial in Russia and Internationally. Sputnik-V vaccine is also undergoing Phase III trial in India in collaboration with Dr Reddy Laboratories. This vaccine was first to get approval for Covid-19 on 5 Aug, 2020. The Phase III data of this vaccine is yet to publish. The approval of this vaccine has drawn criticism in the medical community due to inadequate data on safety and efficacy. Phase I/II trial recruited about 38 subjects each to receive vaccine candidate. Additionally, a small Phase II trial of 110 subjects older than 60 years is underway. A Phase III trial of about 40,000 subjects at multiple sites in Russia is underway. Outside Russia, Sputnik-V is being tested in Belarus, UAE and India. The Russian Direct Investment Fund (RDIF) announced the vaccine was 92% effective in interim trial results based on 20 participants, but these results have not yet been peer reviewed. Results from the two small Phase I/II trial published in The Lancet appears to show the vaccine has a good safety profile and induced strong humoral and cellular response in the subjects. Two doses at an interval of 21 days are to be administered intramuscularly.
NVX-CoV2373: NVX-CoV2373 from Novavax is a protein based vaccine candidate engineered from the genetic sequence of Covid-19 virus. It was created using “Novavax” recombinant nanoparticle technology to generate antigen derived from the coronavirus spike protein. Novavax completed enrollment of 15,000 subjects in a pivotal Phase III clinical trial being conducted in UK to evaluate safety and efficacy of this vaccine. Interim data from this study is expected in first quarter of 2021. More than 25% of subjects in this trial are over the age of 65 years, while a large population of participants had underlying coexisting medical illness generally representative of the population. Novavax expects to begin it Phase III clinical trial in US and Mexico in coming weeks. The data of Phase I trial published in New England Journal of Medicine showed favorable safety profile of this vaccine.Two injections at an interval of 21 days are to be given for desired efficacy.
Besides above listed vaccines, several other are under various stages of development. The race of developing an effective and safe vaccine is on the war footing. Another challenge that is being discussed is related to the logistics of vaccine supply and distribution. All the vaccine will require cold chain transportation between +2 to +8 degree Celsius. Pfizer’s BNT 162b2 would require storage and shipment at -70 degree Celsius. This further complicates the distribution system especially in developing countries and peripheral areas. The preparations for dealing these challenges are being handled by various agencies with assurance of providing good quality vaccine. UK has already started mass vaccination program in the general population. USA has also started mass vaccination from 14 Dec. India is equally getting ready at all levels of society with prioritization of patient population, development of mobile app for ease of tracking and access, and ensuring cold chain logistics at every step.
Besides developing vaccines, people are desperately looking for an effective treatment for this disease. Many strata of the society, government and non-government organizations, research Institutes, pharmaceutical companies and medical fraternity are tirelessly working to get solution to this public health issue.