Enteric fever caused by Salmonella enterica serovar Typhi (S.Typhi) and Salmonella enterica serovar Paratyphi (S. Paratyphi), is a common cause of morbidity in the world, especially in South and Southeast Asia [1,2,3]. In 2015, an estimated 17 million cases of typhoid and paratyphoid fever occurred globally, mostly in South and Southeast Asia and sub-Saharan Africa. Typhoid and paratyphoid fever may be fatal if left untreated with an estimate of 178,000 deaths worldwide in 2015 [4, 5].
The global burden of Disease Study estimated that in 2017, 14.3 million cases of typhoid and paratyphoid fever occurred globally, where 12.6% of the cases occurred in children below 5 years and 55.9% occurred in children younger than 15 years of age [6]. A recent study conducted in Asia and Africa aimed to compare the proportion of children with enteric fever in the age groups < 5 years, 5–9 years and 10–14 years. The proportion of typhoid cases found in < 5 years age group ranged from 14 to 29%, in those 5–9 years of age the range was 30 to 44% and in 10–14 years of age the range found was 28 to 52% [7, 8]. School-aged children above 5 years of age have been reported to have high rates of enteric fever with incidence rates up to four times higher than adult populations [8, 9].
The highest incidence of typhoid fever was found in impoverished, overcrowded regions with poor sanitation such as urban slum areas of North Jakarta (Indonesia), Kolkata (India) and Karachi (Pakistan) [1, 10]. The persistence of typhoid in many low- and middle-income countries in Asia and Africa is due to contamination of water supply by human waste [11, 12].
The symptoms of typhoid fever are highly variable which may be mild, characterized by low grade fever and malaise. It may however cause severe life-threatening systemic infection with multiple complications such as intestinal perforation, intestinal haemorrhage and encephalopathy [13]. Typhoid treatment consists of antibiotics; however, an increasing number of drug-resistant strains have been found in endemic countries that prolong treatment and make it costly [14].
Improvement in sanitation and provision of clean water contributed to a decline in typhoid fever cases in developing countries during the early twentieth century. However, this change was not significant in countries where typhoid fever remains endemic and antibiotic resistance is on the rise. Vaccinations play an important part in the measure to reduce the burden of disease [15, 16].
Current available typhoid vaccines, parenteral Vi-polysaccharide (Vi-PS) and live oral Ty21a are not licensed for infants and toddlers. Vi-PS vaccines are poorly immunogenic in children below 2 years whereas Ty21a is currently available only in enteric-coated capsules, which makes it impractical for infants and toddlers [14, 17, 18]. These existing vaccines can provide 50–70% protection for 3–5 years in individuals over 2 years of age, however considering the above shortcomings, the necessity for the development of Typhoid Conjugate Vaccines (TCVs) was felt. The 2017 WHO Strategic Advisory Group of Experts on Immunization (SAGE) recommended the introduction of TCVs for infants and children aged > 6 months in typhoid endemic countries [3, 19]. TCVs provide longer- lasting protection, higher efficacy, require fewer doses and are suitable from infancy that allows them to be incorporated into the routine immunization program [15, 20].
An example of TCV is Typbar-TCV (Vi-polysaccharide conjugated to Tetanus toxoid), manufactured by Bharat Biotech International Limited, which through their 3- phase clinical trial, proved that it was safe, well tolerated and induced a robust and long-lasting response across age groups for long periods of time [17, 20, 21]. In addition to Typbar-TCV, which is a WHO prequalified vaccine, there are 3 other TCVs licensed in India. A Vi- tetanus toxoid conjugate vaccine from PedaTyph which showed satisfactory results with significant immunogenicity post vaccination [14]. The first prototype TCV was developed by US NIH and they conjugated Vi to recombinant exotoxin A of Pseudomonas aeruginosa (Vi-rEPA vaccine) that has been proven to produce a strong immune response in infants and toddlers [7, 17]. A clinical trial in Philippines studied the safety and immunogenicity of a vaccine with Vi- polysaccharide conjugated to Diphtheria toxoid (Vi-DT). Their phase I trial was conducted on subjects 2–45 years of age and their phase II trial was conducted on subjects 6 to 23 months. Both these phases of clinical trial proved that Vi-DT is safe, well-tolerated and immunogenic for the above age groups [22, 23].
This paper is a continuation of a previously published Phase I study involving subjects aged 2–5 years and 18–40 years as well as Phase II study involving subjects 6 to < 24 months [24, 25]. Although the phase II trial in subjects 2 to 11 years and 6 to < 24 months were held at the same time, the reports of these two age groups are being published separately due to some differences. First, there is no licensed Typhoid vaccine for children below 2 years in Indonesia, hence the control used in this age group was inactivated poliovirus vaccine whereas in children 2–11 years, the control used was an already licensed Vi-PS vaccine. Second, our phase I trial did not include children below 2 years therefore extra care had to be taken in this age group with 2 additional visit conducted, which was not the case in other age groups. Third, the objective of the trial in 6 to < 24 months group was safety and immunogenicity of Vi-DT vaccine whereas the objective of the trial on children 2–11 years was to compare safety and immunogenicity of Vi-DT to an already licensed vaccine. The results of the Phase I trial and phase II trial in children 6 to < 24 months proved that Vi-DT vaccine is safe with mild to moderate adverse effects and immunogenic with a significant increment in antibody GMT post vaccination. Hence, this study aims to evaluate the safety and immunogenicity of Vi-DT vaccine in children 2 to 11 years of age.