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Immunogenicity and reactogenicity of aninactivated hepatitis A vaccine in Indianadults

K. DAS, A. JAIN, R. K. GUPTA, P. KAR

ABSTRACTBack/fTound. In India, a possible decrease in the prevalence

of anti-HA V (hepatitis A virus) antibodies in adults has increasedtheir susceptibility to HAV infection. We evaluated the immuno-genicity and reactogenicity of an inactivated hepatitis A vaccineadministered in a 3-injection protocol.

Methods. Thirty-five healthy adult volunteers, seronegativefor anti-HAY IgG, were administered 720 ELISAunits/ml of theinactivated hepatitis A vaccine intramuscularly at days 0, 30 and180. Anti-HA V IgG was determined at days 30, 60, 90 and180 to assess the efficacy of the vaccine and adverse reactionswere noted to evaluate its reactogenicity.

Results. The mean (SO) age of the volunteers was 33.1(12.3) years and the man:woman ratio was 19: 16. An overallseroprotection of 37.2% (13/35) was obtained at day 30,57.1 % (20/35) at day 60 and 85.7% (30/35) at day 90. Byday 180, all the vaccinees (35/35; 100%) achieved protectiveseroconversion. The vaccine in general was well tolerated and noserious side-effects were observed. Only 8.6% (3/35) of sub-jects developed minor self-resolving adverse reactions such aslocal pain, erythema and/or low-grade fever.

Conclusions. The inactivated hepatitis A vaccine in a three-injection protocol (0, 30 and 120 days) issafe, well tolerated andhighly immunogenic in adult Indian subjects.Natl Med J India 1999; 12:268-9

INTRODUCTIONIndia is endemic for enterically-transmitted diseases includinghepatitis A virus (HAV) infection. In addition to a large numberof inapparent or asymptomatic infections, about 60%-70% ofclinical hepatitis in children below 15years of age is due to HAV.ISerological studies in the past have shown that most adults inIndia acquire anti-HA V IgG due to sub-clinical or clinical expo-sure early in life.' Clinical hepatitis A is therefore believed to berelatively rare in the adult Indian population. A few decades ago,a similar situation was prevalent in many developed countries.However, due to improvement in environmental conditions, sev-eral European countries' such as Spain," Greece,' Italy" andPortugal? have witnessed a reduction in the incidence and preva-lence of hepatitis A. Some recent preliminary Indian reports-?suggest that the prevalence of protective anti-HA V IgG hasdecreased. This decrease will expand the pool of susceptibleadults and could result in an increase in the incidence of the

MaulanaAzadMedicalCollege,BahadurshahZafarMarg,NewDelhi 110002,India

K.DAS, A. JAIN, R. K.GUPTA,P. KAR DepartmentofMedicineCorrespondenceto P. KAR,DIIIM-2755,NetajiNagar,

NewDelhi 110023,India

© The National Medical Journal of India 1999

THENATIONALMEDICALJOURNALOFINDIA VOL. 12,NO. 6,1999

infection.'? It is necessary to evolve strategies to counteract thispossible increase of hepatitis A.

The inactivated hepatitis A vaccine has many advantages overimmunoglobulins. It has been found to be highly immunogenicand extremely safe in several countries.":" Unfortunately, it hasnot been evaluated adequately in Indian subjects and till date, onlya single study" has been reported. Therefore, we evaluated theimmunogenicity and reactogenicity of the inactivated hepatitis Avaccine in a group of adult Indian volunteers.

SUBJECTS AND METHODSSubjectsBetween May 1996 and May 1997, 135 healthy volunteers ofeither sex, without any symptoms suggestive of hepatobiliarydisease, were enrolled after written informed consent. The initialevaluation was done using a questionnaire followed by a completeclinical examination along with biochemical tests for liver func-tion. Anti-HAV IgG was tested by an immunoenzymatic method(ELISA) using a commercially available kit (Hepavase A, GeneralBiologicals, Taiwan). Only seronegative volunteers (351135;25.9%) were included in the study. The presence or absence ofanti-HAY IgG was determined by comparing the absorbancevalue of the sample to the cut-off and the latter was calculatedfrom the absorbance values of the positive and negative controlsas per the manufacturer's guidelines. Specimens with absorbancevalues less than or equal to the cut-off were considered reactivefor anti-HA V IgG, while those with absorbance values greaterthan the cut-off were considered negative. Specimens with absor-bance values within ±10% of the cut-off value were re-tested induplicate.

Administration of vaccineThe 35 seronegative subjects received the inactivated hepatitis Avaccine with a potency of 720 ELISA units/ml (EU/ml) intramus-cularly using a 3-injection protocol at days 0, 30 and 180.

Evaluation of immunogenicityBlood samples were collected from all vaccinees at days 30, 60,90 and 180 and the anti-HAV IgG was determined to assess theefficacy of the vaccine.

Evaluation of reactogenicityAll subjects were evaluated for 12 hours after each dose of thevaccine for any adverse reaction using a standard questionnaire.Side-effects such as fever, local pain, headache, nausea andvomiting were specifically enquired about and a complete exami-nation was carried out for detection of erythema, induration or anyother abnormal physical signs. All subjects were given vaccinecards to note any late adverse effects of the vaccine.

RESULTSThe mean (SD) age of the volunteers studied was 33.1 (12.3) years(range 18-60 years) and there were 19 men and 16 women. Aseroconversion rate of 37.2% (13/35) was obtained at day 30,57.1% (20/35) at day 60 and 85.7% (30/35) at day 90. By day 180(even before the administration of the final dose of the vaccine),all the vaccinees had seroconverted. There was no difference inthe seroconversion rates with respect to age or sex of the vaccineesat any time during the study.

The vaccine was well tolerated and there were no serious side-effects. Only three volunteers developed local pain, erythemaand/or low-grade fever following administration of the first dose

DAS et al. HEPATITIS A VACCINATION IN INDIAN ADULTS

of the vaccine. These subsided spontaneously without any medi-cation.

DISCUSSIONThe epidemiology of HAV infection in India, at least in the urbanpopulation, seems to be changing. In 1982, Arankalle et al. 13 hadreported the prevalence of anti-HAY IgG in Pune to be 95%,reflecting an epidemiological pattern of high endemicity. Incontrast to this, two recent studies from Mumbai" and New Delhi?reported seroprevalence rates of 78% and 71.2%, respectively.This change in the epidemiological pattern of HAV infection, ifconfirmed, is likely to increase the disease burden, and may leadto community outbreaks and thus increase health care costs.Hence, active immunization using a hepatitis A vaccine assumessignificance. Although information on the cost-benefit ratio ofhepatitis A vaccination is lacking, IS the recently observed trend ofdecreasing seroprevalence suggests that such a strategy may berequired, at least in the urban population.v"

The inactivated hepatitis A vaccine used by us has beenevaluated extensively and found to be safe, well tolerated andhighly immunogenic. I 1.12.16-18 However, it has not been evaluatedin Indian adults.

We found that all the subjects seroconverted by day 180, evenbefore the administration of the final dose of the vaccine. Theseresults compare favourably with the seroconversion rate of98%-100% reported in studies conducted elsewhere.l=" How-ever, seroconversion was low at day 30 (37.2%) and day 60 (57%)compared to the >95% rate achieved in trials carried out in otherparts of the world.'>" We did not find any difference in theseroconversion rates related to the age or sex of the vaccinees atany time during the study. This observation is consistent with theresults reported in the literature.v-" The slow seroconversion ratein our subjects during the initial stage of vaccination may be dueto ethnic or geographical factors or due to other unknown reasons.Many workers have used a double dose (1440 EU/ml) andobtained 96% and 100% seroconversion at day 15 and day 30,respectively.P:" It would be interesting to evaluate whether ahigher dose of the vaccine results in faster seroconversion inIndian subjects.

In terms of reactogenicity, the vaccine was found to have agood tolerance profile and no major side-effects were observed.Only 3 out of 35 (8.6%) subjects developed local pain, erythemaand/or low-grade fever after the first dose and these resultscompare favourably with the results of previous studies.":"

Thus, the inactivated hepatitis A vaccine in a 3-injectionprotocol (0, 30 and 180 days) is well tolerated and highly immu-nogenic in adult Indian subjects. However, a cost-benefit analysisof hepatitis A vaccination needs to be performed before a vacci-nation programme is recommended for a wider population inIndia.

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