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Recently, advertisements of the so called first Indian
Vi conjugate typhoid vaccine (Vi conjugated with Tetanus Toxoid as
carrier–PedatyphR) appeared in
Indian Pediatrics. However do we have enough data to start using it? After
going through available data on conjugate Vi vaccines in general, another
Vi conjugate vaccine (Vi conjugated with the non toxic recombinant
exotoxin A of the Pseudomonas aeruginosa as carrier–Vi-rEPA) which
has been tested in field efficacy trials and data available from the
product monograph of PedatyphR, I have following points to
ponder(1-5):
Serologic correlates of protection: Unlike many
vaccine preventable diseases, serologic correlates of protection are not
available for typhoid disease or typhoid vaccines. Hence, even though
typically more than 90% of vaccinees achieve seroconversion after
unconjugated Vi vaccine, efficacy is actually 50-70% in field efficacy
trials(1). Thus one necessarily needs field efficacy trials to conclude
the protection provided by any typhoid vaccine and can not rely on
immunogenicity data alone. While field efficacy trials have been conducted
for Vi-rEPA vaccine, no such clinical efficacy trials have been conducted
for PedatyphR. The vaccine is
licensed based only on immunogenicity data, that too only a single study
involving few hundred Indian subjects (Product Monograph, BioMed Pvt.
Ltd.).
Field efficacy of Vi conjugate vaccines: Szu,
et al.(2) successfully conjugated Vi antigen with the non
toxic recombinant exotoxin A of the Pseudomonas aeruginosa leading
to the development of the vaccine Vi-rEPA, field efficacy for which has
been shown to be nearly 93% at 27 months follow up using 2 doses in
children of 2-4 years of age(2,3). However this vaccine is different from
PedatyphR where Vi is conjugated
using tetanus toxoid as carrier protein. Hence, one can not presume or
extrapolate similar efficacy using different conjugate carriers and
techniques. Even for Vi-rEPA vaccine, there is no efficacy data in
children below 2 years leave aside infants as young as 3 months and yet
PedatyphR is recommended for use from 3 months of age onwards.
Bridging studies: One can bridge the
immunogenicity data of a new vaccine with the efficacy data of an existing
vaccine, provided one tests the new vaccine in the same population using
same antibody testing technique as was applicable for the existing
vaccine. However, this can not be applied to PedatyphR
for two reasons. First of all, serologic correlates of protection are not
known for Vi typhoid vaccines, and hence one can not extrapolate efficacy
of Vi-rEPA vaccine (for which efficacy data are available) with the
PedatyphR vaccine (for which only immunogenicity data are available).
Secondly, these two vaccines are made using different carrier proteins and
different conjugate techniques, and are tested in different population
using different techniques for testing antibody levels; PedatyphR is
tested in Indian population whereas it is compared for efficacy with
Vi-rEPA vaccine which was tested in Vietnam and using different technique
for measuring antibody levels. Just to compare, from our Hib experience we
know that all Hib conjugate vaccines did not compare in efficacy e.g.
PRP-D Hib conjugate vaccine had inferior efficacy than PRP-T vaccine.
PedatyphR
data and product monogram: The
only study done on PedatyphR vaccine is on 169 Indian subjects > 12
weeks old for safety and 145 for immunogenicity, compared to a control
group of 37 children > 2 years old given Vi vaccine studied for safety and
29 for immunogenicity; totally unmatched for number of subjects (and
obviously for the age group). To best of my knowledge, the study is
neither published in peer reviewed journal nor available for critical
review. The only source of data is the product monograph and even there
the data available is piecemeal and not complete. The safety and
immunogenicity data are not available for the subjects receiving
unconjugated Vi vaccine (control) arm for comparison with those receiving
PedatyphR vaccine. Again, one is misled to believe that PedatyphR vaccine
is same as the Vi-rEPA vaccine by repeated highlighting the work done by
Szu, et al.(2) and Kossaczka, et al.(3) (which
is for Vi-rEPA vaccine), stating field efficacy data of Vi-rEPA vaccine
(which is different from PedatyphR and then linking it to PedatyphR which
in fact is totally different vaccine then the Vi-rEPA.
To conclude, it will be more reassuring to have direct
clinical efficacy data with PedatyphR
which will make us more confident to use the vaccine in our day to day
practice.
References
1. Engels EA, Matthew EF, Joseph L, Michael LB. Typhoid
fever vaccines: a meta-analysis of studies on efficacy and toxicity.
British J Med 1998; 316: 110-116.
2. 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.
3. Kossaczka Z, Lin FY, Ho VA, Thuy NT, Bay PV, Thanh
TC, et al. Safety and immunogenicity of Vi conjugate vaccines for
typhoid fever in adults, teenagers, and 2- to 4-year-old children in
Vietnam. Infect Immun 1999; 67: 5806-5810.
4. Lin FY, Vo AH, Kheim HB, Trach DD, Bay PV, Thanh TC,
et al. The efficacy of a salmonella typhi Vi conjugate
vaccine in two-to-five-year-old children. N Engl J Med 2001; 344:
1263-1269.
5. Richard LG, Margaret KM. Polysaccharide conjugate typhoid vaccine. N
Eng J Med 2001; 344: 1322-1323. |
