India’s COVID-19 Shot
In less than six months after the SARS-CoV-2 made its debut in Wuhan in China, more than a hundred COVID-19 vaccine projects have been initiated across the world. India too is pulling out all stops to develop a vaccine against SARS-CoV-2 and is spearheading around 30 vaccine efforts aimed at containing and eventually eradicating the contagion.
While Jenner’s legacy of protective immunity against the ‘speckled monster’(smallpox) continues both in principle and practice, the tricks of vaccine-making have changed for the novel ‘spiked monster’. Indian COVID-19 vaccine efforts consist of newer technology platforms, including virus-like particles (VLPs), peptides, viral vectors, nucleic acid vaccines and recombinant subunit proteins.
Interestingly, many of the licensed vaccines currently in use were not developed using these cutting-edge technologies. But to fight the novel coronavirus, India’s vaccine-making contingent is marching ahead to the beat of a different drum. In addition, India is conducting trials for the BCG vaccine to explore its protective immunity against COVID-19.
A successful COVID-19 vaccine would train the human immune system to create antibodies and neutralise the virus to stop infection without resulting in a disease. Such a vaccine could be developed using the whole virus, viral DNA or RNA, and viral proteins.
Whole virus vaccine
Whole virus vaccines are of two kinds: inactivated and live attenuated. Scientists either use a killed virus (inactivated) or give the whole virus a makeover (live attenuated) so that it would not cause disease, but it would still be recognised by the immune system and produce antibodies against its surface proteins.
The first step in making inactivated or live attenuated vaccines is to isolate the virus. The National Institute of Virology (NIV), Pune, reported the first isolation of SARS-CoV-2 strain in India from nasal and throat swabs of a person with travel history from Italy and his close contacts in March 2020. It soon announced a partnership with Bharat Biotech International Limited (BBIL), Hyderabad for developing an indigenous ‘Make in India’ COVID-19 vaccine candidate. It is speculated that NIV-BBIL will work on developing an inactivated version of SARS-CoV-2 as a vaccine candidate.
A live attenuated COVID-19 vaccine candidate is being co- developed by Serum Institute of India and Codagenix Inc,USA using what is known as the viral genome deoptimization technology. Computer algorithms are used to deoptimize the coronavirus genome in a way that it replicates very slowly in the host cells and therefore does not cause a disease. The deoptimised coronavirus is grown in cells and tested on animals for studying immune response. This stage is called pre-clinical testing. In an interview to The Hindu, Adar Poonawalla, CEO, Serum Institute of India states, “Our vaccine-virus strain is identical to the original virus and can generate a robust immune response.” According to him, the vaccine is expected to be ready by early 2022.
A similar approach is being used by Indian Immunologicals Ltd (IIL) together with Griffith University, Australia. But they have adopted the codon deoptimization technology to develop live attenuated COVID-19 vaccine candidates. “As this vaccine will be a live attenuated vaccine, it is expected to be highly effective by providing very strong cellular and antibody immune responses against the virus,” says Prof. Suresh Mahalingam, Griffith University. IIL will conduct phased clinical trials for the live attenuated SARS-CoV-2 vaccine and hopes to launch it in the market by late 2021.
CoroFlu is a one- drop intranasal COVID-19 vaccine being developed at University of Wisconsin-Madison (UWM) and Flugen Inc in collaboration with Bharat Biotech. Scientists at Flugen have made changes in the flu virus by deleting a gene called M2 such that the virus can multiply itself only once and hence the name – M2SR or M2 ‘self-restricted’. Flugen vaccine design involves insertion of SARS-CoV-2 spike protein into the M2SR ‘vehicle’ to produce a COVID-19 vaccine candidate. A single round of viral replication in a human cell will be sufficient to produce coronavirus proteins but without actually causing infection. The human immune system will recognize these proteins as ‘foreign’ and trigger an immune response to counter it.
Coroflu is based on a flu vaccine whose safety and tolerance will be verified in phase I and II clinical trials. FluGen and UWM researchers hope to complete animal testing by September 2020 and transfer the manufacturing processes to Bharat Biotech to scale up production and to conduct human trials.
Viral vector-based vaccines
Viruses have sophisticated machinery that allow them to enter host cells. Scientists have found ways to construct what are known as viral vectors which retain this machinery. These vectors are able to enter cells but cannot replicate (or replicate just once) once inside because the genes that help in viral replication have been deleted. Such viruses can be used as carriers to transport coronavirus spike or membrane proteins into cells .Once the protein is unloaded in a cell it acts as an immunogen to generate immune response.
This viral vector technology is being used by the Serum Institute of India and the University of Oxford to develop a vaccine called ChAdOx1 nCoV-19. The vaccine is a weakened version of common cold adenovirus which carries the SARS-CoV-2 spike protein sequences. ChAdOx1n CoV-19 vaccine has been shown to work in monkeys and is currently under phase I human trials with over 1,112 healthy volunteers recruited for the study. The University of Oxford has merged phase II and III trials for speedier assessment of safety and efficacy of ChAdOx1 nCoV-19. These trials are expected to end by November 2020. ChAdOx1 nCoV-19 was renamed as AZD1222 after it was licensed to drugmaker AstraZeneca. Serum Institute of India recently signed a licensing deal with AstraZeneca to mass produce 1 million doses of AZD1222 at an estimated price of 1000 INR/dose. According to Poonawalla, “Oxford vaccines will be made and packaged in India.” He adds that the Serum Institute of India is spending more than $100 million for this facility.
A different approach is being taken by BBIL and Thomas Jefferson University (TJU), USA. They have developed a COVID-19 vaccine candidate called CORAVAX™. TJU has used a deactivated rabies vaccine as a vehicle for SARS-CoV-2 spike proteins to produce CORAVAX. “Our vaccine candidate, CORAVAX™, is made from part of the current coronavirus and that is combined with another proven vaccine that serves as a carrier of sorts,” informs Matthias Schnell, Director of the Jefferson Vaccine Center to TJU news. Currently, TJU is collecting data on animals vaccinated with COROVAX. Bharat Biotech will begin human trials for COROVAX by December 2020.
Zydus Cadila’s European research unit at Etna Biotech is developing a COVID-19 vaccine based on a carrier measles vaccine produced with reverse genetics technology. Coronavirus proteins will be inserted into a live attenuated recombinant measles virus (rMV) vectored vaccine. The rMV vaccine is already tested for safety, efficacy and protection against measles infection in animal and human trials. The vaccine candidate is in a preclinical stage.
Virus like particles (VLPs)
Premas Biotech is developing a “Triple Antigen Vaccine” based on the Virus like particle (VLP) approach. It involves assembling viral proteins to form virus-like structures and has been successfully applied for the development of HPV and hepatitis B vaccines.The triple antigen vaccine prototype consists of multiple versions of three proteins from SARS-CoV-2 assembled into a VLP. The aim of this vaccine is to trick the immune system to produce antibodies without exposing the body to the actual virus. Premas is currently developing scale up designs and applying to regulatory bodies for starting animal testing for their vaccine candidate.
The genetic code of the novel coronavirus can theoretically be used to make DNA-based vaccines. This is being adopted by Zydus Cadila’s DNA vaccine effort against the SARS-CoV-2 membrane protein, and is listed by WHO in the ‘Draft landscape of COVID-19 candidate vaccines’. The vaccine is currently in a preclinical stage. Zydus Cadila’s DNA vaccine contains a set of instructions or genetic code for building coronavirus membrane protein. Upon entering human cells, the DNA sequence instruction will be read and converted into the viral protein. The immune system will elicit a defense response against this coronavirus protein. So far DNA vaccines have been approved for animal diseases, but not for humans. An advantage of a DNA vaccine is that it could be mass produced quickly as compared to traditional vaccines.
Protein Subunit vaccine
A subunit vaccine uses a part of coronavirus protein as an immunogen to evoke immune response. Mynvax, a pharma start-up incubated at the Indian Institute of Science (IISc), Bangalore, is developing a protein subunit based COVID 19 vaccine. Mynvax is currently testing several SARS-CoV-2 spike protein subunit vaccine candidates in animal models to identify the best in terms of immune response and protection. In an article published on COVID Gyan, Raghavan Varadrajan, co-founder, Mynvax says that the company is trying to find ways to make the subunit candidates more immunogenic so that the amount of antibodies produced is sufficiently high to protect against infection in most people. Mynvax estimates a time of eighteen months to start phase I trials.
Repurposing old BCG vaccine
In recent weeks there has been plenty of debate on the protective immune boosting properties of the BCG vaccine against COVID-19. Serum Institute of India, the exclusive license holder of the VPM1002 BCG vaccine, secured funding from Department of Biotechnology (DBT), Govt of India, and started the phase III human trial at N Naidu Infectious Diseases Hospital, Pune in May 2020. Three categories of human volunteers have been included in the study: coronavirus suspects, positive symptomatic and positive asymptomatic cases. These high-risk volunteers will be compared with placebos (volunteers not receiving the BCG vaccine) to test VPM1002 for preventive efficacy and ability to diminish clinical severity of the COVID-19 disease. Poonawalla, according to an article in The Print hopes that the vaccine could hit the market by the end of this year if the study yields positive results.
While some vaccine candidates are potential frontrunners, a few are definitely promising, and some projects, though premature, are breathing life. India and the rest of the world is trying to conquer or shorten the COVID-19 vaccine development timeline. However, one can not rule out delays because animal and human testing are of critical importance in vaccine development. We must consider the failure rates of human clinical trials with scientific rigour and not with panic and despair. It is difficult to predict which candidates will work because of considerations such as safety, efficacy, immunogenicity, cost, scale-up, distribution, mass immunization and so on. Each vaccine effort holds the promise of both success and failure. The path to a COVID-19 shot is perilous, yet we need to pin our hopes on these arduous efforts as the saying goes, “All roads lead to Rome.”
Adita Joshi is Director, Sansriti Foundation, New Delhi. She also works as a Scientific Consultant with CSIR-IGIB.