Inside the making of India’s first HPV vaccine

The world’s largest vaccine maker had planned to inaugurate the park with the production of the human papillomavirus (HPV) vaccine, India’s first indigenously made one a month ago. HPV infections are among the most common sexually transmitted diseases and as such vaccines can prevent many related cancers such as cervical cancer.

But then, Covid-19 changed its course. A part of the facility was used to make Covid vaccines.

The pandemic is over and now, the focus is back on the HPV jab that promises to drive down prices of similar vaccines from foreign manufacturers. The vaccine, named Cervavac, was launched on 1 September and will be released soon.

The vaccine was part of a grand vision SII’s Chief Executive Officer (CEO) Adar Poonawalla set for himself and the company. That vision included building products with world-class capability and around serious diseases such as cervical cancer, malaria and tuberculosis – products with the potential for global impact.

According to a 2020 estimate published in The Lancet, cervical cancer is the second most common cancer among women in India, causing over 75,000 deaths every year. At roughly 120,000, India accounts for a fifth—and the largest proportion—of total cases in the world. More than 80% of cervical cancer cases in India and around 70% worldwide are caused by two high-risk types of HPV: 16 and 18. According to the National Cancer Institute, the US government’s lead agency for cancer research and training, HPV is a group of more than 200 related viruses and about 14 high-risk HPV types.

While routine cervical screening (Pap test) is a preventive strategy, transmission of the disease can only be prevented through widespread vaccination, making it the primary prevention measure. But existing vaccines are not a mass-market phenomenon. Their uptake in India has been low so far.

There are two vaccines available in the Indian market: Gardasil and Gardasil 9, manufactured by MSD (Merck & Company in the US). Gardasil is effective against four types (6, 11, 16 and 18) and comes with a hefty price tag. 3,500. at around 10,000, Gardasil 9 is the most recent; It is effective against nine HPV types (6, 11, 16, 18, 31, 33, 45, 52 and 58).

“Cost is a major factor that has limited the introduction of HPV vaccines in low- and middle-income countries,” says Dr. Gagandeep Kang, professor of gastrointestinal sciences at Christian Medical College, Vellore. He agrees with the cheap, readily available HPV vaccine. Can “control and reduce” cervical cancer.

This is where SII’s Cervavac could prove to be a game changer. It has been shown to be as effective as Gardasil against HPV types 6, 11, 16 and 18 during trials, says Dr Hit Sharma, a scientist at the company. And it would be available for about one-third the price of Gardasil in the private market and one-tenth that for the government.

“The vaccine will be available for the first time in the private market in April-May at a cost of Rs. 1,000-1,500 per dose,” says Poonawalla. Four-five million doses are expected to be supplied in 2023. SII will then scale up the capacity to 60-70 million doses thereafter. Annual production will eventually stabilize at around 140 million doses. Hopefully. We can start exports from 2025,” says Poonawalla.

Science

The rapid pace at which the Covid vaccines were made has given a wrong impression about the process of vaccine development. Vaccines usually have a gestation period of 10-15 years.

After Harald zur Hausen’s discovery of the cervical cancer-causing virus strain during 1980–84, which won him the Nobel Prize in Medicine in 2008, it took seven years to lead to HPV vaccines. Researchers Ian Fraser and Jian Zhou replicated a portion of the virus into virus-like particles (VLPs), the building blocks for the HPV vaccine. Since receiving the license in 1995, it took nearly a decade for Merck & Co to come up with a commercial vaccine. The British multinational pharmaceutical company GSK plc soon followed suit.

Unlike drugs, vaccines do not have their own “generics”. Therefore, even though SII entered the HPV vaccine field several years later than MSD and GSK, there was no ready-made recipe available for its duplication and mass production. The company had to develop its own processes.

In 2011, SII imported ‘platforms’ (clones of yeast) from Germany and shut down the process. The yeast platform is where the VLPs for the different types of HPV are expressed and isolated. But it involves several steps whose conditions had to be figured out by SII scientists through trial and error over many years.

The first step is fermentation (a biochemical process), where a cellular culture (yeast) is grown. In one batch of production, a small 1.5 ml vial containing cellular material is converted into 120 liters of broth over several days. The pH conditions, amount of dissolved gases, etc. are optimized here to get the exact yield.

Scientists then isolate VLPs from this broth over a few days, and further purify them. The purified material, now just three to eight litres, is tested for its physical and chemical properties and finally poured into polypropylene bottles.

There are four different bottles of VLPs, corresponding to the four different types of HPV, that need to be mixed. Before this can happen, additional components (adjuvants) are added to enhance the immune response and stability of the vaccine. This process is called ‘formulation’, which is one of the most important steps in making a vaccine. Scientists at SII painstakingly found the right ingredients and conditions for the formulation. Once the different types of admixtures are thoroughly mixed, and show sufficient consistency, they are sent to automated filling stations.

Thanks to abundant labor and advanced infrastructure, SII cannot mass-produce vaccines to its Western rivals. This brings down the cost. However, this alone does not explain the low cost. SII vials often contain multiple doses – this goes up to 10 doses for Covishield, which is the Covid-19 jab – which reduces the cost of manufacturing, packaging, storage and distribution.

It is not just a matter of professional practice but of correct scientific formulation. Because vaccines are easily susceptible to microbial contamination, preservatives need to be added to allow multiple withdrawals from a vial. And finding the right combination of preservatives took some time and effort.

testing

It took two-three years for SII to finalize the correct formula for HPV vaccines and to carry out pre-clinical studies, which was completed in 2014 by Syngene International Limited (a subsidiary of Biocon) in Bengaluru and Eurofins Advinus Pvt. Ltd.’s laboratories. -15.

Initially some tests were done on rats and rabbits. Dr. Sharma explains, “Since the HPV vaccine will be given to girls and women of childbearing potential, its reproductive toxicity (effect on fertility) was also demonstrated.”

SII then submitted the relevant report to the Central Drugs Standard Control Organization (CDSCO), the regulatory body, and sought permission for human trials, which began in 2017.

The first human trial was in a healthy adult population aged 18–45 years, not the target population (adolescent girls and boys, for example, are part of the target population for the HPV vaccine). This was conducted by Syngene among 20-30 volunteers who were followed for 30 days. Their blood samples were also taken to study biochemical parameters. Volunteers are monitored for any serious adverse events. “One or two women reported blood in their urine, but it turned out to be remnants of blood from their periods,” says Dr. Sharma. Investigators decided the vaccine is safe, he says.

The SII team then requested to conduct Phase 2 and 3 trials to expedite the process. This can be done in cases where the manufacturers are certain about the safety of the vaccine. Phase 2 trials were conducted in October 2018 at 10 sites in India involving approximately 600 subjects. It was successfully concluded by January 2020, which showed that the efficacy of Cervavac was similar to that of Gardasil.

The efficacy of HPV vaccines is measured in terms of the body’s immune system response. And several studies have shown 98-100% seropositivity (presence of antibodies in a blood sample) to Gardasil, even many years after vaccination.

The third trial was delayed due to the pandemic, and SII had to enroll new subjects due to the pandemic. In total, 1,700 subjects participated at 12 sites in India. The study concluded in March 2022 without any major complications—no side effects other than mild pain and fever were reported.

The CDSCO had given marketing approval to SII’s vaccine on 12 July. Two doses at six-month intervals are recommended for the 9-14 age group. Three doses are recommended for people between the ages of 15 and 26. The second and third are to be given two and six months after the first dose, respectively.

SII received support from India’s Department of Biotechnology (DBT), the Bill & Melinda Gates Foundation (BMGF) and the Biotechnology Industry Research Assistance Council (BIRAC) established by the World Health Organisation, the International Agency for Research on Cancer. It received financial assistance of up to $9 million from DBT and BMGF. The cost of the project is approximately $100 million.

roll out

In the past, the older HPV vaccines in India have been mired in controversy. Seven deaths were reported during a study among 23,000 girls in Andhra Pradesh and Gujarat in 2007–10. While the study and the vaccines received a lot of bad press, and were suspended in 2010, a government investigation found no link between the deaths and the vaccinations.

“Upon deeper investigation, it was found that the deaths were not related to vaccination (for example, drowning), but issues related to the way the study was conducted, even though the vaccine was safe and licensed,” says Dr. Kang.

The episode raised a lot of skepticism among the people, which both SII and the government may have to accept once a new vaccine comes out.

But one thing is certain – Cervavac’s potential could allow it to become a part of government vaccination programs not only in India but across the world. Since the initial quantity will be less, the Government of India may defer the implementation of the Universal Immunization Program (UIP) by six months or more. Immunization against 12 vaccine preventable diseases is provided free of charge under UIP. Price for government procurement will start at 300-400 can also go below 300 once demand goes up, says Poonawalla.

All vaccines administered under government programs are for children, except for the Covid, tetanus and adult diphtheria (Td) vaccines. Adult vaccination under UIP is not common in India. Will girls and women come forward?

“Pediatric vaccination programs are successful because women, especially when they don their mother’s hat, make sure their children get vaccinated,” says Poonawalla. For their girls, boys and themselves,” he says.

Boys and men can also get the HPV vaccine to protect themselves against genital warts and cancer of the anus, penile and oropharyngeal (head and neck).

As a major segment of the target population will be youth, SII is open to exploring channels such as social media to reach them. Perhaps, bring a celebrity on board to create awareness. “We already have it in our mind, but we don’t want to reveal it now. You will hear a lot more about it when the time comes,” smiles Poonawalla.