The recent conference presentations and advertisements
for ‘indigenous’ conjugate typhoid vaccine prompt the following
considerations.
Is typhoid a significant public health problem in India to merit
vaccination?
(a) It is usually taken for granted that
typhoid is a major public health problem in developing countries.
However, careful analysis of data from current(1) and previous
studies(2) shows that the absolute incidence of blood-culture proven
typhoid episodes is only about 0.2% per year and, it contributes to a
very small proportion of the total febrile episodes across all age
groups (Table I). This is a very important
observation because vaccination can/will protect only against typhoid
episodes and not febrile episodes believed to be typhoid and/or loosely
labelled ‘enteric fever’ and treated as typhoid.
(b) Increasing antibiotic resistance(3) is
often cited to emphasize the public health significance of typhoid.
However, the latest multi-centric international study reported
resistance in India to be less than 10% to chloramphenicol, ampicillin,
trimethoprim - sulphamethoxazole, combination of all three, and
ciprofloxacin; and about 2% to ceftriaxone, but almost 60% to nalidixic
acid(1). For unexplained reasons, bacterial resistance in India was much
lower than other developing countries in the region; if true, this
further reduces the public health significance of typhoid.
(c) The National immunization schedule
included two doses of typhoid vaccine at school entry over two decades
back; however this was not based on robust evidence and was abandoned.
Changes in living conditions, hygiene practices, sanitation etc since
then must also be factored-in if/when typhoid vaccination is considered
in the present day.
Does conjugate typhoid vaccine merit consideration in India?
(a) The main advantage of vaccine(s) with
polysaccharide antigen(s) conjugated to proteins is the stimulation of
T-cell dependent immune responses. The implication of this is that
infants with relatively less mature immune systems would respond, which
does not happen with polysaccharide alone. This would be a major benefit
only if the disease (here typhoid) is a significant problem among young
infants. This is often implied in literature by calculating the absolute
number or relative proportion of typhoid cases among infants(1,2).
However, it is more important to assess the importance of typhoid (and
hence prevention) as an issue of public health significance rather than
only as a clinical problem. Table 1 constructed from
latest data(1) shows that typhoid is responsible not only for a very
small proportion of febrile episodes in infants, but the proportion is
less than in older children. Therefore, based on current information the
conjugate vaccine has limited role in the Indian context, although this
is the exact opposite of what is suggested(1). It should be noted that
this conclusion need not be similar for other developing countries(4).
(b) The other purported advantage of typhoid
conjugate vaccine is the belief that it confers superior protection as
compared to the currently available vaccines. A recent Cochrane
review(5) reported protective efficacy of 48% (95% CI=34-58%) at 2.5-3.0
years with three doses Ty21a vaccine; 55% (95% CI=30-70%) at 3.0 years
with one dose Vi-polysaccharide vaccine and 87% (95% CI=56-96%) at 2.3
years with two doses Vi-rEPA (conjugate) vaccine, giving the impression
that the conjugate vaccine is superior. However it is inappropriate to
draw conclusions by comparing data between studies; the superiority of
conjugate vaccine (if any) needs to be established through a randomized
controlled comparative trial, rather than assumption by extrapolation.
TABLE I
Significance of Typhoid in India
Age-group |
Febrile
episodes/
100,000/y |
Typhoid
episodes/
100,000/y |
Contribution of
typhoid episodes
among total
febrile episodes |
< 2 years |
13920 |
89.2 |
0.64% |
2-4 years |
12040 |
340.1 |
2.82% |
5-15 years |
9490 |
493.5 |
5.2% |
> 16 years |
6620 |
119.7 |
11.7% |
Overall |
7690 |
214.2 |
2.79% |
Data from the
latest multicentric study (1) |
Current status of conjugate typhoid vaccine
(a) A Vi-rEPA conjugate vaccine prepared in
USA was reported to have excellent protective efficacy in clinical
trials conducted in Vietnam nearly a decade back(6). However, this
vaccine also underwent clinical trials in China simultaneously;
inexplicably the data is not available in the public domain. It is also
surprising that no subsequent clinical trials have been reported with
the vaccine.
(b) An Indian manufacturer has reportedly
developed and tested a Vi-TT conjugate vaccine, but the trial design,
outcome-measures, reporting format and conclusions are of questionable
validity and more data is required to draw a definite conclusion.
What can we conclude?
Need for a vaccine is determined by clearly
understanding disease burden (not synonymous with number/frequency),
epidemiological factors and public health significance. Data on
effectiveness (does the vaccine protect?), efficacy (does the vaccine
generate immune responses?) and safety, should guide decisions once the
need is justified. Using/recommending/promoting vaccine(s) merely because
they are available in the market(7) relegates science to the background.
In the context of typhoid conjugate vaccines, the need, effectiveness and
efficacy have not been clearly established; hence it cannot be recommended
at present.
References
1. Ochiai RL, Acosta CJ, Danovaro-Holliday MC, Baiqing
D, Bhattacharya SK, Agtini MD, et al. A study of typhoid fever in
five Asian countries: disease burden and implications for controls. Bull
WHO 2008; 86: 260-268.
2. Sinha A, Sazawal S, Kumar R, Sood S, Reddaiah VP,
Singh B, et al. Typhoid fever in children aged less than 5 years.
Lancet 1999; 354: 734-737.
3. Kumar S, Rizvi M, Berry N. Rising prevalence of
enteric fever due to multidrug-resistant Salmonella: an epidemiological
study. J Med Microbiol 2008; 57: 1247-1250.
4. Saha SK, Baqui AH, Hanif M, Darmstadt GL, Ruhulamin
M, Nagatake T, et al. Typhoid fever in Bangladesh: implications for
vaccination policy. Pediatr Infect Dis J 2001; 20: 521-524.
5. Fraser A, Goldberg E, Acosta CJ, Paul M, Leibovici
L. Vaccines for preventing typhoid fever. Cochrane Database Syst Rev 2007,
Issue 3.
6. Szu SC, Stone AL, Robbins JD, Schneerson R, Robbins
JB. Vi capsular polysaccharide-protein conjugates for prevention of
typhoid fever: preparation, characterization, and immunogenicity in
laboratory animals. J Exp Med 1987; 166: 1510-1524.
7. Indian Academy of Pediatrics Committee on Immunization (IAPCOI).
Consensus recommen-dations on immunization, 2008. Indian Pediatr 2008; 45:
635-648. |