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Indian Pediatr 2019;56: 453- 458 |
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Opportunities for
Typhoid Vaccination in India
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Manikandan Srinivasan1,
Kulandaipalayam Natarajan Sindhu1,
Jacob John2 and
Gagandeep Kang1
From 1Division of Gastrointestinal
Sciences and 2Department of Community Health, Christian
Medical College, Vellore, India.
Correspondence to: Dr Gagandeep Kang, The Wellcome
Trust Research Laboratory, Division of Gastrointestinal Sciences,
Christian Medical College, Vellore 632 002, Tamil Nadu, India.
Email: [email protected]
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Typhoid fever, an infection with potentially life
threatening complications, is responsible for 11 to 21 million illness
episodes and 145,000 to 161,000 deaths each year globally. India is a
high burden country and also faces the challenge of antimicrobial
resistance, which further narrows treatment options. This review
analyzes the need for typhoid vaccination in India, and appraises the
evidence on efficacy, immunogenicity and cost-effectiveness of currently
available typhoid vaccines. In 2018, WHO prequalified the first typhoid
conjugate vaccine Vi-TT and recommended it for children aged 6-23
months, along with measles vaccine at 9 or 15 months of age through the
expanded programme on immunization. With the high endemicity of typhoid
in India and the proven cost-effectiveness of the conjugate vaccine, a
roll-out of typhoid vaccine should be considered at the earliest.
Keywords: Community, Immunization, Implementation, Prevention.
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T yphoid fever is caused by
Salmonella enterica serovar typhi or Salmonella typhi, which
spreads by the feco-oral route of transmission,
through a combination of short and long transmission cycles. The Joint
Monitoring Programme 2017 update report has estimated that worldwide,
two billion people use drinking water from a source contaminated with
faeces and 2.3 billion people do not have access to safe sanitation [1].
Typhoid is endemic in low- and middle-income countries (LMIC) where the
widespread implementation of well-engineered water and sewage systems is
yet to be achieved. Globally 11 to 21 million cases of typhoid fever
occur annually, resulting in 145,000 to 161,000 deaths, with a
substantial burden in South Asia [2]. Modelled estimates have shown that
3.6 (1.5-9.4) million cases of typhoid fever occur annually in South
Asia [3]. In India, the pooled incidence of typhoid fever was reported
to be 377 (178-801) per 100,000 person-years, with highest incidence in
children aged 2 to 4 years [4]. The Disease of the Most Impoverished
(DOMI) program in Asian countries in 2001-04 reported a typhoid
fever-related hospitalization rate of 8.8%, with most hospitalizations
in children between 5 and 15 years [5]. Intestinal perforation, a
serious complication in inadequately treated typhoid fevers, can have a
case fatality rate of 15% [6].
The DOMI study highlighted the magnitude of
Multi-drug resistance (MDR) to first-line antibiotics, namely,
chloramphenicol, ampicillin and co-trimoxazole. Pakistan had a high
proportion of resistance, with 65% of its S. typhi strains
isolated being multidrug resistant, followed by Vietnam (22%) and India
(7%) [5]. The H58 clade, a dominant, MDR haplotype of S. typhi,
circulating in Asia and Africa over the last 25 years is a serious
concern [7]. Since 2016, extended drug resistance (XDR) typhoid cases
(resistant to fluoroquinolones and third generation cephalosporins in
addition to first line antibiotics) have been reported from Pakistan,
and this is an impending threat for other countries [8].
Well-engineered water and sanitation systems,
effective treatment of cases and carriers, food hygiene measures, and a
pragmatic vaccination programme have demonstrated a decrease in burden
of typhoid fever [9]. Water, sanitation and hygiene (WASH) interventions
carry multiple benefits beyond typhoid prevention. However, their
implementation is expensive and takes time, particularly in
resource-constrained LMICs.
In the year 2000 and 2008, WHO recommended typhoid
vaccination in high-burden countries, including India [10,11]. Further,
in 2018, the Strategic advisory group of experts on immunisation (SAGE)
upheld its view on programmatic implementation of typhoid vaccines in
endemic countries [12], and WHO additionally prequalified one typhoid
conjugate vaccine (TCV) which has the Vi polysaccharide conjugated to
tetanus toxoid (Vi-TT) [13]. In this article we critically analyze the
currently available options for typhoid vaccination in India and the
need for the introduction of the vaccine into the National immunization
program.
WHO-Recommended Typhoid Vaccines
Three WHO prequalified typhoid vaccines are currently
available: live attenuated Ty21a, Vi capsular polysaccharide (ViPS) and
TCV vaccines.
Ty21a, Vi Capsular Polysaccharide Vaccines
Both Ty21a and ViPS vaccine have demonstrated
efficacies of 50% in large field trials and possess a good safety
profile as per Global Advisory Committee for Vaccine Safety (GACVS) (Table
I). The need for booster doses and the fact that these vaccines
were not licensed for use in younger children, limits the potential for
their use in national programs.
TABLE I Comparison Of Ty21a, Vi Polysaccharide and Typhoid Conjugate Vaccines
Characteristics |
Ty21a |
Vi Polysaccharide |
Typhoid conjugate vaccine (Vi-TT)[13] |
Type of vaccine |
Live attenuated
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Polysaccharide subunit
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Polysaccharide with a protein conjugate |
Licensure, place and year
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Europe in 1983
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USA in 1994
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India in 2013
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Currently licensed formulation
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Enteric capsule
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Liquid
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Liquid |
Route and dose of administration |
Oral; 3-4 doses on every second day |
Intramuscular; single dose |
Intramuscular; single dose |
Common side effects |
Transient fever and gastrointestinal symptoms |
Transient fever, erythema and local pain |
Fever, pain and swelling |
Recommended age-group |
Individuals older than 6 y
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Individuals aged 2 y and above |
Individuals aged 6 mo and above upto 45 y. |
Cumulative efficacy at 3 y [28] |
51% (95% CI: 36-62%) |
55% (95% CI: 30-70%) |
-
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Herd effect
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30%
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44% (95% CI: 2-69%)
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- |
Time taken to demonstrate protective immunity
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7 d from the last dose |
7 d after vaccination |
- |
Correlate for protection |
• Serum IgG anti-O seroconversion
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Serum IgG anti-Vi antibody level of at
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Serum IgG anti-Vi antibody level of 1000
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• Rise in IgA antibody titres: 7 d after the
last dose |
least 1 µg/mL
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Elisa Units and above [29] |
Need of revaccination |
• Highly endemic countries: every 3 -7 y |
Every 3 y
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No sufficient evidence*
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• Travellers (from non-endemic to endemic
area): every 1-7 y (as per the existing national policies) |
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Precautions |
• Not to be co-administered for individuals who are on
antibiotics / anti- malarial therapy |
Known hypersensitivity to the components of vaccine
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Known hypersensitivity to the components of vaccine |
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• Known hypersensitivity to the components of vaccine
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*Not presently recommended. |
Typhoid Conjugate Vaccines (TCV)
TCV has a capsular polysaccharide (Vi) covalently
linked to a protein conjugate such as recombinant exoprotein of
Pseudomonas aeruginosa (rEPA), tetanus toxoid, diphtheria
toxoid or cross reactive material 197 (CRM197). Linkage of a protein
moiety results in T-cell dependent differentiation of B cells. Thus,
TCVs are able to mount a robust immune response in children aged less
than 2 years, rendering the vaccine highly immunogenic and suitable for
use in this age group [14]. Currently, the Drug Controller General of
India has licensed three Vi-conjugated vaccines. The features of Vi
vaccines are detailed below:
Efficacy: Vi-TT and ViPS were evaluated in adults
in a controlled human infection model and demonstrated a vaccine
efficacy of 54% and 52%, respectively, with the end-point of persistent
fever of ³38ºC
for 12 hours or longer or S. typhi bacteremia. Among those
with fever of ³38ºC,
preceding a S. typhi bacteremia, the efficacy of Vi-TT and
ViPS was 87% and 52%, respectively [15]. An efficacy trial for Vi-TT
vaccine in children aged 6 months to 12 years at Kolkata showed a
vaccine efficacy of 100% [95% CI: 97.6 -100] when 2 doses of the vaccine
were administered at a 6- week interval [16], although boosters are not
now recommended.
Higher seroconversion and avidity: Vi-TT
demonstrated higher seroconversion rate (100%) when compared to ViPS
(88.6%), 28 days following vaccination [15]. In an Indian trial, in
individuals aged between 2 and 45 years, Vi-TT had a significantly
higher seroconversion rate than ViPS (97.3% vs. 93.1%; P<0.01)
at six weeks post-vaccination [17]. A two year follow-up showed antibody
titers to be significantly higher in Vi-TT group when compared to ViPS
group (74.1% vs. 53.3%; P<0.001) [12]. The avidity of
antibodies (Avidity Index >60) following a booster dose was superior in
Vi-TT recipients (46%) compared to ViPS (16%) vaccines [12]. Conjugate
vaccines not only demonstrate a better seroconversion rate and a longer
antibody response when compared to ViPS, but also offer greater avidity
(Web Table I).
Higher immunogenicity of TCV in children aged <2 y:
A Vi-TT trial in Indian children aged between 6 and 23 months
demonstrated a seroconversion rate of 96.8% (95% CI: 92.1-99.1) and
65.1% (95% CI: 56.1-73.4) at 6 weeks and 2 years, respectively after
vaccination. Even after 5 years, antibodies persisted in over 70% of
Vi-TT vaccinees. Children of both age groups, 6-11 and 11-23 months,
showed a robust immune response [12].
Sero-efficacy: The Vi-TT trial also determined
the sero-efficacy, which was 85% (95% CI: 80-88%) [18].
Co-administration with EPI vaccines:
Co-administration of Vi-TT and measles or measles-mumps-rubella (MMR)
vaccines at 9 or 15 months of age showed no interference with antibody
response to any antigen [12].
Safety: In 2018, SAGE acknowledged the safety
profile of Vi-TT in children, but GACVS reports on post-marketing
surveillance will provide more evidence on its safety [12].
Cost-effectiveness analysis of Vi-TT: Vaccination
is ‘cost saving’ if cost of the vaccination program is lesser
than the costs involved in treatment of cases. On the other hand,
vaccination is ‘very cost-effective’ if cost-effectiveness (CE)
ratio is less than the per capita gross national income (GNI) and ‘cost-effective’
if less than 3 times the per capita GNI.
CE of Vi-TT (priced at US$ 1 per dose) was analyzed
in Delhi and Kolkata from a healthcare payer perspective under the
following strategies: (i) Routine immunisation (RI) with TCV (9
months); (ii) RI + catch up vaccination (9 months–5 years); (iii)
RI + catch up vaccination (9 months–15 years); (iv) RI + catch up
vaccination (9 months–25 years); and (v) RI + catch up
vaccination (all ages more than 9 months). In Delhi, compared to no
vaccination, both RI with TCV (strategy1) and RI + catch up at all ages
(strategy 5) were ‘cost saving’ strategies with a probability >99%. In
Kolkata, compared with no vaccination, RI with TCV (strategy 1) was
‘very cost effective’ with >75% probability. On imputing the current
market price of Vi-TT at a unit price of 1800 INR in the analysis, it
was found that none of the above strategies were ‘cost effective’ at
Kolkata. However, at Delhi, RI with TCV (strategy 1) was still ‘cost
effective’ at the same unit price of the vaccine, and this may be due to
higher costs incurred in treatment of cases [19].
Typhoid-endemic LMICs are classified based on annual
incidence, as low (10-50 cases/100,000 population), moderate (50-200
cases/100,000 population), and high (>200 cases/100,000 population).
Considering the annual incidence of typhoid, CE of Vi-TT in LMICs was
analyzed using two strategies: (i) RI in infants through EPI, and
(ii) RI through EPI + one time catch-up campaign in school-aged
children (5-14 years). Results showed that RI of infants through EPI
(strategy 1) would be ‘cost effective’, if annual incidence is
>50/100,000 population, and the second strategy of RI + one time catch
up would be ‘cost effective’, if annual incidence of typhoid is
>130/100,000 population [20]. These analyses thereby show that use of
typhoid vaccines is indeed ‘cost effective’, provided vaccine delivery
is strategically planned as per the geographic heterogeneity of disease
distribution across different age groups.
Beyond Typhoid Fever Control?
In South-East Asia, considering the significant
burden of typhoid, clinicians perceive undifferentiated acute febrile
illness as suspected typhoid fever, and treat it empirically with
antibiotics. It is estimated that, for every case of blood culture
confirmed typhoid fever, three to 25 febrile patients without typhoid
illness receive antibiotics, which could have been potentially avoided.
This over-treatment with antibiotics can result in antimicrobial
resistance (AMR) towards commonly used antibiotics, thereby compelling
the use of higher antibiotics. Routine CEA involving vaccines, while
considering the costs of illness from both societal as well as health
care payer’s perspective, leaves out potential benefits of avoiding
overtreatment with antibiotics. Thus, using TCV to reduce typhoid burden
can eventually bring down the prescription rates of antibiotics
attributed for treating suspected typhoid fever cases [21], and
potentially prevent emergence of antibiotic resistance.
Recent Recommendations
In 2018, SAGE recommended a single dose of Vi-TT for
children aged less than 2 years, either, along with initial dose of
measles vaccine at 9-12 months of age or with the second dose of measles
vaccine at 15-18 months. For children aged more than 2 years, SAGE
continued its prior recommendation of either ViPS or Ty21a according to
the country’s immunization policy: although, Vi-TT likely offers longer
duration of protection when compared to ViPS or Ty21a and hence, can be
potentially considered for use in older children as well [13]. Further,
in 2018, the Indian Academy of Pediatrics recommended a single dose of
TCV for children from 6 months onwards, without any subsequent booster
dose [22].
Following WHO’s prequalification of Vi-TT in 2018,
the GAVI Alliance agreed to provide a support of US$ 85 million towards
introduction of TCV in 2019 in developing countries [23]. Following
this, the manufacturer of Vi-TT vaccine has stated its willingness to
reduce the price of Vi-TT from US$ 26 (1800 INR) per dose to US$ 1.5
(100 INR) per dose for GAVI eligible countries [24]. This significant
cost reduction of Vi-TT will be an important factor to be considered by
policymakers in India.
What Comes Next?
Country-level data in the Indian context on burden of
typhoid fever among children is likely to be available from an ongoing
Surveillance for enteric fever in India (SEFI) by 2020 [25]. In
addition, the Typhoid Vaccine Acceleration Consortium (TyVAC) has begun
a trial to study the effectiveness of TCV among children in Bangladesh,
Malawi and Nepal [26]. The Navi Mumbai municipality has begun a campaign
of TCV immunization in two rounds in July 2018, and vaccine
effectiveness will be evaluated by a consortium including the Indian
Council of Medical Research [27]. Thus, data on typhoid disease burden
and effectiveness of TCVs are awaited, which will serve as strong
evidence to aid the government to consider typhoid vaccine.
Conclusion
Typhoid burden is associated with considerable
heterogeneity in distribution, and hence the decision on vaccination and
its strategies for delivery should be based on local epidemiology.
Vi-TT, with its unique advantage of being amenable for use in children,
aged less than two years through routine immunization can decrease
disease burden. With antimicrobial resistance looming large in Asia,
this is a crucial time for India to consider introduction of typhoid
vaccine into the national immunization programme at the earliest.
Contributors: JJ, MS: conceptualized the article;
MS, KNS: reviewed the literature, drafted and revised the manuscript
under the overall support and supervision of JJ and GK. All authors
approved the manuscript for publication.
Funding: None; Competing interest:
None stated.
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