Typhoid Fever is an enormous public health problem. Annually, the disease is responsible for approximately 20 million cases of febrile illness and more than 100,000 deaths. The infection is caused by salmonella enterica (serotype typhi) and typically presents with fever, headache and gastrointestinal symptoms. Deaths are typically due to intestinal haemorrhage or perforation. For more than a century, vaccines have been relied upon to prevent the spread of disease. Unfortunately these have had limited effect since components of the bacterial cell wall used in the vaccine only promote a very limited immune response. In recent years a conjugate vaccine, combining polysaccharide chains from the bacteria and a highly immunogenic tetanus toxoid protein, has been developed in an attempt to overcome this. The impact of the new vaccine was recently tested in Nepal and published in the New England Journal of Medicine. In this post we summarise the study and talk to Buddha Basnyat, one of the lead authors, about typhoid fever in his country and the impact that such a vaccine is hoped to have.
In the autumn of 2017, 20,019 children in Kathmandu were randomised to receives one of two conjugate vaccines - typhoid (T) or meningococcus A (M). Over the course of a year, 45 cases of typhoid were identified with blood cultures. Those who were given the typhoid vaccine were 82% less likely to develop the infection - just 7 cases (0.07%) (T) compared to 38 (0.38%) (M). This reduction was consistent with earlier research and importantly, considerably better than that found with previous typhoid vaccines.
The impact of the vaccine can be explained by the strong immune response that it produces. A total of 1343 children gave blood samples in the days following the vaccination. These demonstrated that seroconversion, defined as an antibody titre that more than quadrupled within 28 days after vaccination, occurred in 99.1% of those who received the typhoid vaccine compared to just 2.1% who did not. Although the long term efficacy of this vaccine is not known, these results encouraged the authors to write,
"Conjugate vaccines ... are expected to provide longer-term protection, unlike the protection provided by polysaccharide vaccines, which generally last for only 2 to 3 years"
Importantly, the vaccine was also found to be safe. The vast majority of adverse effects were minor and their frequency similar to that of other conjugate vaccines.
Rose Spots are found in approximately one third of patients who develop typhoid fever. These are irregular, blanching and macular. Typically, they are found on the trunk and disappear after 3 to 4 days
Thanks Buddha for talking to us. Congratulations on completing such an important study. In your forward to Dr John Dickinson's A Yak In The Fridge you mentioned that studying typhoid fever came naturally to you. Can we start by asking you about your experience of treating the disease?
From about 1980 (when John Dickinson was my mentor) until now I have dealt with typhoid fever except during my time abroad in Calgary, Alberta and Phoenix, Arizona. This is a biblical, poor man's disease but very gratifying to treat. Amazingly the disease is still rampant today in South Asia (population 1.8 billion) with incidence rates > 500 per 100,0000 population (anything >100 per 100,000 is significant). It is both highly preventable and treatable (although antimicrobial resistance is posing a big challenge).
Is there a comprehensive vaccination programme in Nepal? In particular, do Nepali's have access to a typhoid vaccine? Has this been effective? What impact do you think this new vaccine will have?
Yes, Nepalis have access to typhoid vaccine but like everyone else in South Asia, they have to pay for it. Amazingly for such a rampant illness with effective vaccination (the polysaccharide vaccine with about 60% efficacy has been available for decades) for prevention, there is no comprehensive, free (or subsidized) government vaccination programme accross the region in South Asia (not just in Nepal). The new conjugate vaccine which we trialed near Patan Hospital was found to be >80% effective and we are working with the government of Nepal and GAVI (the Vaccine Alliance) to use this vaccine for a comprehensive immunization programme in Nepal. If we are successful in convincing the government, it will clearly have a tremendous impact upon the control of this widespread infectious disease.
Typhoid Fever is most commonly found in sub-Saharan Africa and South East Asia (red - strongly endemic, brown - endemic, grey - sporadic)
Were you surprised to see how effective the trial vaccine was?
I was surprised that we reached the pre-determined sample size of about 45 culture positive patients with typhoid fever in the first year of the trial to be able to carry out an interim analysis and publish the results of our randomized controlled trial. You never know with vaccination trials, the disease sometimes just goes down in the midst of the trial and the study fizzles out, like it happened elsewhere with the zika vaccine trials.
The immune response of the conjugate vaccine was very impressive. How long do you hope it will provide protection for? Could it give lifelong immunity?
I think it lasts at least 6 years but we need to study this some more. If it is lifelong immunity, that would be wonderful. It is important to note that all of these important immunological aspects of infectious diseases like typhoid fever are now more interesting for many people because of the Covid-19 pandemic and the importance of an effective vaccination.
You must have been very happy to find such low rates of side effects. Do you think a conjugate vaccine will be well received by the people of Nepal? What are the most significant barriers that stand in the way of all Nepali children receiving the vaccine in the future?
Yes, indeed Nepalis will be very happy to receive this typhoid vaccine because almost all (in fact I would say most people in South Asia) have heard about typhoid fever or suffered from it. In fact, any undifferentiated fever gets an initial typhoid fever label by everyone including healthcare professionals. The reason is simple - people still live in neighbourhoods that Charles Dickens described in his famous novels of the Victorian era in England. So you can imagine, a lot of fecal-oral transmission of disease. The general sanitation needs to be overhauled to overcome diseases like typhoid. This overhaul is going to take time. So in the meantime, South Asian governments including Nepal need to actively and comprehensively use the typhoid conjugate vaccine. The most significant barrier is the inertia displayed by these governments in tackling this rampant problem when the disease is so obvious.
Cases of Typhoid Fever are now rare in developed countries. However a century ago things were quite different. Between 1907 and 1915, Mary Mallon "Typhoid Mary" (4th on the right) became the first person in the USA to be identified as an asymptomatic carrier. It was believed that she infected at least 51 people. She would eventually die at the age of 69 after many years of isolation
Thanks Buddha for speaking to us!
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