Memories of the COVID-19 pandemic are still fresh. The pandemic plunged the world into an unprecedented situation – lockdowns, clampdowns on global travel, disruptions of economic activity, mass migration of people and the deaths of millions. It did, however, have a silver lining – the quick development of a slew of vaccines against COVID-19 and mass vaccination drives to prevent further casualties and illnesses.
Indian research institutes and vaccine manufacturers responded to the emergency and came up with a bouquet of vaccines that helped save lives not only in India, but in many countries across the world. The pandemic also invigorated the global scientific community to look for ways to address similar situations in the future. Scientists believe new vaccine technologies are going to help the world cope with future pandemics.
The evolution of vaccine-making
Over the past century, vaccine-making technologies have undergone a sea change. Among the early physicians and doctors who pioneered vaccines was Edward Jenner. In 1796, he noticed that people infected with cowpox were immune to smallpox. People treated with material collected from a cowpox sore did not get infected with smallpox, he found. Hence, the word ‘vaccine’, derived from vacca – the Latin word for cow.
Over the next few decades, this knowledge led to the development of smallpox vaccines. Then, Louis Pasteur developed a post-exposure vaccine to treat rabies caused by dog bites.
The modern era of vaccines began with the flu vaccine during the First World War, to combat the Spanish flu that killed an estimated 50 million people around the globe. This was followed by the Yellow Fever vaccine and other vaccines to address childhood and adult infectious diseases such as whooping cough, polio, diphtheria, and measles.
Combined with universal immunisation programmes advocated by the World Health Organization and UNICEF, childhood vaccines are helping save millions of lives every year. Many diseases like smallpox and polio have been successfully eliminated, and diseases like plague, cholera and typhoid have become challenges of the past. India’s Universal Immunisation Program (UIP) for instance, covers over 26 million newborn children and 30 million pregnant women every year.
Traditional methods to make vaccines involve the use of either attenuated (weakened) organisms or inactivated (killed) organisms. These vaccines are based on the principle that by exposing pathogens to the air or chemicals, they can be attenuated, and then used to trigger an immune response in the human body. Similarly, disease-causing viruses are inactivated by removing their harmful genetic material and are then used as vaccines, as they are still capable of evoking the desired immune response from the human body. Vaccines based on this principle are generally called ‘killed vaccines’ as they don’t make use of the whole disease-causing organism but are based on inactivated toxins, virus particles or conjugates. The immunity imparted by vaccines based on inactivated viruses, such as the tick-borne encephalitis vaccine and the hepatitis A vaccine, is effective but may be transient. Therefore, booster doses are required for such vaccines. Overall, for several decades, life-saving vaccines for children have been either of the killed or attenuated type.
Genetic engineering in vaccines
The next big development in vaccine technology came from new developments in genetic engineering. Such vaccines deployed cell culture and used a re-assortment of viral genetic material instead of using attenuated or killed viruses. Genetic engineering made it possible to clone or replicate ‘foreign’ DNA in a host or a living cell. This technique came to be known as recombinant DNA or rDNA. The idea was to produce antigens outside an infectious agent, thus eliminating the risk associated with using live pathogens or their parts. This resulted in the development of recombinant vaccines and brought in a new revolution in vaccine technology.
The first rDNA-based Hepatitis B vaccine, developed in 1988, was based on a specific protein of the Hepatitis B virus produced by inserting its genetic code into yeast cells. These vaccines use parts of the viral genetic code that encode proteins found on the virus’s surface. These proteins stimulate the formation of antibodies. This fully eliminated the use of any viral DNA in the vaccine. The technology was commercialised by biotechnology firms like Genentech and Chiron. A decade later, Indian companies, Shantha Biotechnics and Bharat Biotech, developed and launched Hepatitis B vaccines based on genetic engineering technology.
Like the Hepatitis B vaccine, the Human Papillomavirus (HPV) vaccine also contains single protein components of the virus. Such vaccines are referred to as ‘subunit vaccines’. They can protect against virus-induced cancers like cervical cancer.
The mRNA revolution
The COVID-19 pandemic brought to the fore a major advancement in vaccine technology – mRNA technology. In human cells, genetic information that is encoded in the DNA is transferred to messenger RNA (mRNA) that acts as a platform for protein production. Therefore, mRNA plays a pivotal role in generating an immune response of any kind. Because of this, mRNA became a chemical of interest for the development of new immunotherapies and vaccines.
While rDNA vaccines are good, mass producing them quickly poses challenges, since all such vaccines need cell cultures at a massive scale. Scientists have been working on developing mRNA-based vaccines for decades, as mRNA produced outside the body, without cell culture, can be used in vaccines.
In their early work, Katalin Karikó and Drew Weissman – who won the Nobel Prize for Medicine in 2023 — noticed that dendritic cells recognise mRNA (made outside the human body) as a foreign substance and cause the activation and release of inflammatory signalling molecules. This fundamental discovery, published first in 2005, led to the development of vaccines against the Zika virus and MERS-CoV. Since MERS-CoV is closely related to SARS-CoV-2, a new vaccine against COVID-19 could be developed fast. The potential of this technology attracted commercial firms, and by 2010 there were three of them — CureVac, BioNTech and Moderna – with programmes to develop and commercialise therapies for infectious diseases as well as cancer.
In 2017, Moderna started clinical trials of an mRNA-based vaccine against the Zika virus, while BioNTech began clinical trials to evaluate the safety and immunogenicity of their mRNA vaccine candidates against influenza viruses with pandemic potential. When the COVID-19 pandemic broke out in early 2020, these companies quickly developed mRNA vaccines against the virus with help from scientific groups. In clinical studies, vaccines of Moderna and BioNTech showed potent antibody responses as well as memory B cell and T cell responses, protecting against severe disease and death. This demonstrated that mRNA technology could help in the production of vaccines at a speed not matched by other vaccine technologies. Updates could also be rapidly made available as new variants of the virus emerged. In addition, this opened the doors for the development of vaccines and therapeutics against several other infectious diseases and cancers.
The Indian scenario
While fundamental science leads to new ways of developing vaccines, their production on a mass scale requires highly capable companies. Over the decades, Indian companies have acquired the capacity necessary for the production of vaccines meeting global standards and adhering to Good Manufacturing Practices (GMP). Many of them have been cleared by the WHO for the supply of vaccines through international agencies. Given the low cost of production, Indian companies have been supplying billions of doses of vaccines globally. In addition, Indian vaccine firms pioneered new ways to improvise available vaccines so that they could withstand hostile climates without losing their efficacy. This list of vaccines includes traditional ones like DPT or TT, Measles, Mumps, Rubella, Hib, Typhoid, and Rabies; as well as several modern vaccines like Hep-B, Rotavirus, Cholera and Varicella vaccines.
Due to technical strength and industrial capacity built over decades, Indian companies played a key role during the COVID-19 pandemic with vaccines covering all technology platforms. The work on COVID-19 vaccines in India was initiated when the number of confirmed cases in the country was only 57. The National Institute of Virology (NIV), Pune, isolated the virus on 11 March 2020 – the day WHO declared SARS-CoV2 a global pandemic. The first Indian COVID-19 vaccine was Covaxin – a whole virion attenuated vaccine, developed by Bharat Biotech in collaboration with NIV. The second was Covishield which was developed at Oxford University and manufactured by the Serum Institute of India in Pune. It was followed by Zycov-D, a DNA vaccine developed by Zydus Cadila; Corbevax, a receptor-binding domain protein subunit vaccine developed at Baylor College of Medicine and manufactured by Biological E in Hyderabad. Pune-based Gennova Biopharmaceuticals developed an mRNA vaccine, GEMCOVAC, which was also the world’s first thermo-stable COVID-19 vaccine.
Vaccine safety
Despite the rapid development of COVID-19 vaccines helping save millions of lives, the safety of vaccines, whether for COVID-19 or for other diseases, cannot be compromised upon. Vaccine safety is a major challenge given the chances, even if these may be very small, of adverse events. India launched a national Adverse Event Following Immunisation (AEFI) surveillance programme in 1986, following the launch of the Universal Immunisation Programme (UIP) in 1985. However, the first set of operational guidelines to monitor AEFI was released only in 2005 and these were revised in 2010 and further strengthened in 2015. During the pandemic, additional steps were taken for AEFI monitoring relating to COVID-19 vaccines. A special group consisting of medical specialists, cardiologists, neurologists, pulmonary medicine specialists, and obstetrician-gynaecologists was formed to assess the link between vaccination and reported cases of adverse events. The group reported its findings to the National AEFI Committee, which periodically published its reports.
Preparing for the next pandemic
Since the turn of the century, the world has seen several disease outbreaks, epidemics and pandemics – SARS, Zika, Ebola, MERS, bird flu, and COVID-19. With factors like climate change, the increased movement of people and global trade, scientists predict an increasing number of global health challenges. Many infectious and viral agents are new and evolve fast, while older and forgotten pathogens are re-emerging. In such a scenario, effective and safe vaccines remain the only hope.
COVID-19 has propelled the scientific community to develop a new platform to develop vaccines as soon as a new pathogen emerges so that the world can respond to future pandemics. The success and rapidity of the development of COVID-19 vaccines was due to the prior work done with coronaviruses.
Moderna’s work on MERS and other pathogens using techniques for the manipulation of Type 1 surface protein antigens that enabled optimisation of the pathogen to the immune system helped it develop a Covid-19 vaccine as soon as it received the Covid-19 virus sequences. Based on this experience, the Coalition for Epidemic Preparedness Innovations (CEPI) has worked out a systematic approach to vaccine preparedness for future pandemics based on knowledge about viral families. CEPI was founded in 2016 in Davos by the governments of Norway and India, the Bill and Melinda Gates Foundation, Wellcome, and the World Economic Forum.
While viral taxonomy changes almost every week, there are 25 to 30 viral families that are known to cause human disease. By studying them closely and ranking them based on risk (high, medium and low), it is possible to develop prototype vaccines, says Barney Graham of the Vaccine Research Centre at the National Institute of Allergy and Infectious Diseases, United States. If this can be done, the world can have vaccines quickly as soon as a new challenge emerges.
In this approach, a vaccine is developed for the major attributes (transmissibility, lethality) in the given genetic space. If something new emerges from a particular viral family, scientists can adapt very quickly and develop an appropriate vaccine.
CEPI is working with partners to develop a viral vaccine library as well as the operational side of executing clinical trials and adaptation of regulatory policies. CEPI has proposed a 100-day timeframe for vaccine development after a new pathogen emerges. If vaccines become available early on, a new pathogen could be controlled before it causes a pandemic. The process can be quickened if regulators are prepared and informed fully about new technology platforms and also have an understanding of different virus families and safety, immunogenicity and biomarker information in advance.
Along with this, it has been suggested that the world community should consider developing a global emergency authorisation approach, and regional harmonisation of regulatory processes within different regions of the WHO. This could lead to a paradigm shift in combating future pandemics.
(Dinesh C. Sharma is a New Delhi-based journalist and author.)
Published – February 21, 2025 12:26 pm IST