The measles outbreak in Mumbai, followed by Ranchi, Ahmedabad and Malappuram over the past month has drawn attention to the large number of unvaccinated children. Over 16,000 suspected cases have been recorded in India. Of the 20 children who have died of measles since October 26 in the Mumbai Metropolitan Region, just one had been vaccinated – but only with the first of the two-dose course.

As health workers launch an intensive door-to-door campaign to persuade parents to have their children immunised, public health experts point to the threat from another infectious disease for which a vaccine exists but is still not part of India’s free universal immunisation programme.

Typhoid – a water-borne disease that spreads through water and food contaminated with Salmonella Typhi bacteria – kills an estimated 1,28,000-1,61,000 people a year. India accounts for over 40% of these deaths while more than eight million Indians get the disease every year. The bacterial infection causes high fever, weakness, stomach pain and diarrhoea. In severe cases, it can lead to pneumonia or intestinal bleeding and cause death.

In June, an expert sub-committee, under the chairmanship of virologist Dr Gagandeep Kang, recommended that the typhoid vaccine be included in the country’s universal immunisation programme during a meeting of the National Technical Advisory Group on Immunisation, or NTAGI, which advises the government on vaccine-related policy decisions. If not, the committee warned that typhoid could result in 89,300 deaths and cause 46 million cases in the next 10 years, the minutes from the meeting held on June 28 show.

“Indian manufacturers are manufacturing typhoid conjugate vaccine and supplying globally. This is high time that kids in India get that vaccine as India has a huge burden of typhoid fever,” said Dr Sushant Sahastrabuddhe, associate director general at the International Vaccine Institute in South Korea.

A typhoid vaccine can currently be purchased and administered at private healthcare facilities in India. But Dr Jayprakash Muliyil, professor at Christian Medical College, Vellore, said cost remains a prohibitive factor with a single dose priced between Rs 2,000-Rs 2,500. “It is expensive and used by only those who can afford it,” he said. Muliyil is also member of the expert sub-committee in NTAGI.

The high cost has led to poor uptake of vaccine. In 2016, NTAGI recommended the formation of the Surveillance for Enteric Fever in India consortium to assess typhoid burden across India before it could take a call on rolling out the vaccine. Kang and Muliyil were part of it. Kang said their survey at various sites suggested that only 9%-10% of eligible children could pay to get a typhoid shot.

“We have already made a recommendation to include typhoid in routine immunisation,” Kang said. “It is up to the government how and when they implement it.”

If the vaccine is included under the universal immunisation programme and procured in bulk by the government, the cost of a dose could drop to Rs 160-Rs 200, say experts, and it would be available free of cost for public.

Kang said once NTAGI makes a recommendation, the government takes a call on whether and when to launch a vaccine, and sometimes it gets done within weeks or can even take years. In 2014, the rotavirus vaccine was recommended by NTAGI, it was introduced in the universal immunisation programme two years later in 2016. In 2017, NTAGI recommended the human papillomavirus vaccine – which helps prevent cervical cancer – but the vaccine is yet to be rolled out in the immunisation programme.

Most recently, in January 2021, vaccines against Covid-19 were rolled out within days of the NTAGI’s recommendation. “When it comes to vaccines, it is a no-brainer,” said Kang. “The vaccine will prevent several deaths.”

The continued delay in rolling-out the typhoid vaccine in India will not only cause more fatalities, but also increase drug resistance and health expenditure in a country with a large, vulnerable population. Poor families are the most susceptible to typhoid, which spreads through the oral-fecal route in places with poor sanitation and hygiene. It is already endemic in Sub-Saharan Africa and South Asia, and cases of drug resistance are fast spreading in India’s neighbouring country Pakistan.

India's first conjugate vaccine was manufactured by Bharat Biotech. India has approved four vaccines against typhoid till date.

High disease burden in India

The first typhoid vaccine was launched in 1896 in the United Kingdom, mainly for soldiers susceptible to water-borne infections. Early vaccines were made from capsular polysaccharide, an outer layer of a bacterial cell, which was inactivated and processed into a vaccine. But it did not offer long-term protection.

“The polysaccharide vaccines generate immune response through T-cell independent mechanism. Hence the vaccine has to be repeated every three years,” Sahastrabudde said. T-cells are like memory cells that can remember an infection. “Conjugate vaccines (Attaching protein molecule to the polysaccharide) generate T-cell response from the immune system. The immune system can then remember the infection in future and mount an immune response.”

In 2013, manufacturer Bharat Biotech launched the first conjugate vaccine, Typbar-TCV. This vaccine attached a protein subunit with a polysaccharide unit to mount a T-cell response in the body. In 2018, the World Health Organization labelled this vaccine safe and recommended the use of conjugate vaccines in countries with high typhoid burden.

In 2021, Biological E’s TyphiBEV, was the second Indian conjugate vaccine to be declared safe by the World Health Organization. India’s drug regulator, the Central Drugs Standard Control Organisation, has licensed four typhoid vaccines so far, including these two.

Though the typhoid vaccine has been available for decades, the real push to introduce it in India’s universal immunisation programme came in December 2016. After a meeting of the NTAGI, a recommendation was made to conduct a surveillance exercise for typhoid in 18 sites across India. The government formed a consortium called the Surveillance for Enteric Fever in India. It comprised a group of experts, including some from NTAGI, to measure the incidence, burden and drug resistance of typhoid in tier I, II and III cities. It began its study in October 2017.

“Until then, the argument was that water and sanitation had improved so much that we don’t need typhoid vaccine anymore,” said Kang. “When we began to look, we saw this was not the case.”

By World Health Organization standards, the incidence of typhoid is considered “very high” if there are more than 500 cases per lakh population. The consortium found that the typhoid incidence was 575 per lakh population in Delhi, 714 per lakh in Kolkata and as high as 1,173 per lakh population in Vellore. Surveys conducted in hospitals in some cities also found that typhoid incidence was very high in Chandigarh and Anantapur, in Andhra Pradesh. Children younger than 15 years of age were the worst affected across all sites surveyed.

“Very high and high burden in almost all age groups of urban areas and in young adults in rural areas has been estimated,” the consortium reported. Kang said typhoid is vastly under-reported because of the limited diagnostic facilities in rural India.

In 2018, the Indian government also approved a clinical trial to assess the impact of typhoid vaccination in the population. Over 1.72 lakh children aged between nine months and 15 years of age were vaccinated against typhoid in Navi Mumbai by the government. The NTAGI observed that the vaccine was “efficacious” with limited side effects. These findings are similar to other trials in Bangladesh, Nepal and Malawi.

Drug resistance, treatment cost

With the growing resistance of typhoid bacteria to drugs, the lack of immunisation coverage is a matter of concern, the expert committee said during a meeting of the NTAGI in June. Samples from Vellore, Mumbai, Gurgaon, Tamil Nadu showed resistance to widely used antibiotics.

Dr M Imran Khan, a Pakistan-based public health expert who wrote a paper on the hurdles in rolling out the typhoid vaccine, told that most doctors treat the disease without proper investigation. “Since the cost of the treatment is high, the patients do not complete the course and bacterium is exposed to sub-optimal dose of the antibiotics, and hence develops resistance,” he said. Pakistan, he said, is seeing high resistance of typhoid bacteria against antibiotics.

In India, too, there is resistance to drugs, said Dr Veeraraghavan Balaji, the lead author of a study on typhoid trends in India from 2000-’15 that was published in the American Journal of Tropical Medicine and Hygiene. “It is low, but it is there,” he said.

The study found that resistance to the drug ciprofloxacin is almost universal in recent Indian isolates. Ciprofloxacin is widely used for typhoid treatment along with another antibiotic, azithromycin.

Critical care specialist Dr Vishesh Agrawal said that a few years ago he used to see antibiotic resistance in one or two out of ten typhoid cases. “Now, it is five or six out of 10,” he said. Agrawal said azithromycin was used rampantly during the Covid-19 pandemic and now its use continues with people popping it for common cough and cold. “The resistance to it will increase in typhoid treatment.”

An increase in resistance to drugs also adds to treatment costs. Physician Dr Siddharth Lalitkumar said that if the first line of drugs does not work, he has to use more potent intravenous antibiotics. “Treatment cost for outpatient treatment may go up to Rs 15,000,” he said. “If a patient has to be hospitalised, the cost is higher.” He added that typhoid said patients are also taking longer to recover.

Pakistan has already introduced the vaccine in its routine immunisation programme in 2019 with the support of Global Alliance for Vaccines and Immunisation, or GAVI, an international organisation that works to ensure equitable vaccine distribution. In 2019, GAVI supported Zimbabwe to introduce the typhoid vaccine following an outbreak there.

“As I understand GAVI has offered India an opportunity for typhoid introduction,” Kang said. “It is up to the government to apply for it.” Veena Dhawan, joint commissioner-immunisation in the health ministry, did not respond to calls or messages.