THE proportionate mortality rate because of to gastro-intestinal diseases, including typhoid but excluding diarrhoea, is 1.06 per cent, according to the Directorate General of Health Services. The diseases that cause higher proportional mortality than gastro-intestinal diseases are diseases of the cardiovascular system, the respiratory system, perinatal (pregnancy) causes, (other) infective conditions (eg, septicemia), diseases of the cerebrovascular system, injury (excluding drowning), poisoning, diseases of the nervous system, diabetes and complication of hypertension, diseases of the hepatic system, diseases of the renal system, pregnancy complications, multisystem dysfunction, acute abdominal diseases excluding diarrhea and malignancy (different forms of cancer).
About 477,500 cases of typhoid occurred in Bangladesh with 8,000 deaths in 2021. The contributing factors of the disease are rapid urbanisation which cannot match the required drainage and sewerage systems and inadequate sanitation and safe drinking water.
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How typhoid vaccine works
VACCINE against typhoid has been developed since 2018. Two types of typhoid vaccines have so far been prequalified by the World Health Organisation. One is the polysaccharide-only antigen and the other is its conjugated form, which eases uptake of the vaccine. The polysaccharide vaccine, after administration, is engulfed by the immune cells, called dendritic cell, which reside in the skin. The engulfed antigen incites immune reaction. But the generation of this immunity is based only on B-lymphocyte (white blood cell), which produces a weak and short-lived antibody, called Immunoglobulin M. Conjugated vaccine, on the other hand, produces immunity through T-white blood cells mediated immunity in addition to the B-cell mediated humoral immunity. The T-cell mediated immunity produces copious amounts of IgG antibody 鈥� the strongest, largest and longest lasting immunity. T-cell mediated immunity also produces memory cells, which switch back to incite immune reactions very fast, when challenged with specific antigen.
The world鈥檚 first conjugate vaccine for typhoid fever was produced by Bharat Biotech called Typbar. It was prequalified by the World Health Organisation in 2018. Phase I to III clinical trials were done earlier with 1,100 volunteers. In phase IV, 3,500 volunteers were included. Post-marketing surveillance included 10,000 vaccinated individuals. Clinical trial was subsequently done with volunteers: 24,000 in Malawi, 25,000 in Nepal, 50,000 in Bangladesh, 200,000 in India and 250,000 in Pakistan. An interesting point that needs to be noted now is, according to the Bharat Biotech management, Gavi, the Global Alliance for Vaccine Initiative, was 鈥榣ooking forward to working with the countries to support the introduction of this safe and effective vaccine.鈥� In reality, however, Gavi opted for Typhibev for Bangladesh.
Typhibev-TCV, or typhoid conjugated vaccine, manufactured by Biologic-E was compared with Typbar-TCV during Phase II/III trial. It is a recently adopted technique called immununo-bridging, ie if a similar vaccine shows safety and immunogenicity than the vaccine being tested will also be safe and effective. Typhibev-TCV was found to be non-inferior to Typbar-TCV in terms of immunogenicity. Efficacy of Typbar was, however, observed to be slightly better than Typhibev. Although the number of volunteers between phase I and IV trials varied between Typhibev and Typbar, the total number was more or less equal, as per account of Biologic E. The WHO paper referred to here, however, mentions that Biologic E tested the vaccine in 341 volunteers during its three trial phases.
Bharat Biotech claims that a single dose of Typbar offers immunity for five years while Biologic E suggests that Typhibev works for four years. The other differences are given in the table.
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Current typhoid vaccine campaign
VACCINATION campaigns are a delivery strategy to quickly reach large number of vaccinees. Bangladesh aims to reach five crore children with the Typhibev vaccine at one go. It was imperative to ask as to why from the beginning, before its inclusion in the routine programme, this biggest-ever campaign of any vaccine ever in the country has been enunciated on what and whose advisement? It needs to be noted that in India, no typhoid vaccine has yet been included into its routine programme although India鈥檚 National Technical Advisory Group on Immunisation recommended its inclusion in 2022. No such large campaign has even been undertaken in India although India鈥檚 population size is more than eight times that of Bangladesh
TYPBAR vaccine has the following side-effects: (a) serious side effects are allergic reaction, low blood counts, infection, kidney problems, liver problems, pneumonitis, pulmonary edema, thrombosis and death; (b) common side effects are pain or swelling at the injection site, fever, headache, fatigue or tiredness, muscle aches and chills. As Typbev has been claimed to be as good as Typbar, it is apt to be as bad as Typbar also when it comes to that. According to Biologic E, the common side-effects of its vaccine are injection site pain (4.50 per cent), injection site erythema-redness (0.64 per cent) and injection site swelling (0.32 per cent). The most frequently reported systemic adverse events were pyrexia (2.25 per cent), vomiting (0.96 per cent), headache (0.64 per cent), fatigue (0.64 per cent), arthralgia-joint pain (0.32 per cent) and rash (0.32 per cent). Based on the differences of formulation, it is apt to assume that Typhibev side effects should not be any less or any compelling then Typbar, if not more.
The World Health Organisation advised to make adrenaline (epinephrine) injection in 1:1000 dilution (1 mg/mL) to be readily available to manage an acute anaphylactic reaction or for any allergic reaction that may occur due to any component of the Typhibev vaccine. It also advised that vaccinee should remain under medical supervision for not less than 30 minutes after vaccination. Customarily, active pharmacovigilance should be conducted after approval of any new drug or vaccine. To our knowledge none of this has ever been done in Bangladesh. The European Union Parliament interrogated and the Fox TV of the United States which tried to interview Pfizer and Moderna officials, the producers of Covid-19 vaccines, which revealed how sloppily the scientific rigour was followed before the mRNA vaccine, first of its kind, was brought to the market so hurriedly and the Oxford vaccine was withdrawn from the market later.
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Alternative considerations
ALTHOUGH the vaccine is now free, the government will have to procure it from the international market in future. So, its price is an important factor. The price of the conjugated Typbar vaccine and Typhibev vaccine is Rs 1,530 and Rs 1,656 per dose. As is evident, Typbar is slightly cheaper than Typhibev. Why then Typhibev was procured instead of Typbar despite the fact that it has been more thoroughly trialled? In future when Bangladesh will have to procure this vaccine for 3,400,000 children yearly, the cost will be Tk 777 crore. But then, every fifth year the budget will increase incrementally, ie twice, three times, four times and so on, to cover those who will lose immunity after every four years, which will be added to the new vaccinees every year.
This will continue as long as a person runs his life course. On the top of this, the cost of pharmacovigilance and management of vaccine side effects also need to be considered monetarily. On the other hand, the benefit, cost ratio of improvement in sanitation and prevention of all forms of water and food-borne diseases, not only typhoid, compared with typhoid vaccine, has not been considered ever. We also need to consider comparative benefit-cost ratio of prevention, control and management of the diseases mentioned in the beginning, which cause much higher mortality and typhoid vaccine.
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Abu Muhammad Zakir Hussain is chairman of the Community Clinic Health Support Trust and member of the health sector reform commission.
