Cholera vaccine field trials in east Pakistan. 1. Reaction and antigenicity studies. A controlled field trial of plain and aluminium hydroxide-adsorbed cholera vaccines in Surabaya, Indonesia, during 1973--75. A controlled field trial of the effectiveness of various doses of cholera El Tor vaccine in the Philippines. A controlled field trial on the effectiveness of the intradermal and subcutaneous administration of cholera vaccine in the Philippines. The 1968-1969 cholera-vaccine field trial in rural East Pakistan. Effectiveness of monovalent Ogawa and Inaba vaccines and a purified Inaba antigen, with comparative results of serological and animal protection tests. A controlled field trial of the effectiveness of monovalent classical and El Tor cholera vaccines in the Philippines. Controlled field trial of the effectiveness of cholera and cholera El Tor vaccines in Calcutta. A controlled field trial of an aluminum phosphate-adsorbed cholera vaccine in Calcutta. FIELD TRIAL OF CHOLERA VACCINE IN RURAL EAST PAKISTAN. FIRST YEAR OF OBSERVATION. Cholera vaccine field trials in east Pakistan. 2. Effectiveness in the field. Comparative study of reactions and serological response to cholera vaccines in a controlled field trial conducted in the USSR. Report of the 1966-67 cholera vaccine field trial in rural East Pakistan. 3. The lack of effect of prior vaccination or circulating vibriocidal antibody on the severity of clinical cholera. A controlled field trial of the effectiveness of cholera and cholera El Tor vaccines in the Philippines. Preliminary report; Philippines Cholera Committee.
Double-blind controlled cholera-vaccine trials were carried out in rural East Pakistan in 1963 and 1964. Pretrial studies indicated that a whole-cell cholera vaccine of high mouse protective potency, at a dose of 0.5 ml, produced an antibody response and reaction pattern consistent with use in such trials. A purified Ogawa antigen, given at a dose of 100 mug, elicited no adverse reactions and evoked both agglutinating and vibriocidal antibodies against both Inaba and Ogawa test suspensions.In the field, adverse reactions to the cholera vaccines occurred primarily among adults and were observed with both the whole-cell preparation and the purified Ogawa antigen. At the dose used in the field trials (0.4 ml), the reactions elicited by the whole-cell vaccine were acceptable to the population and no more marked than those following the locally prepared typhoid-paratyphoid vaccine. Delayed reactions to the whole-cell cholera vaccine were observed beginning 4 to 7 days after the vaccine was administered; the bulk of them (60%) did not interfere with work at any time; all resolved promptly; and none developed fluctuation or was associated with abscess formation. A controlled field trial comparing the effectiveness of a plain cholera vaccine with that of a vaccine adsorbed to aluminium hydroxide was carried out in a cholera-endemic area of Indonesia during 1973-75. Tetanus toxoid adsorbed to aluminium phosphate was used as the control. In vaccinees aged 1-4 years, the adsorbed cholera vaccine provided about 88% protection for 6 months following vaccination and still provided about 50% protection between 11 and 14 months after vaccination. In the same age group, the plain vaccine provided only 53% protection during the first 6 months and no appreciable protection beyond that period. In those aged 5 years and over, both vaccines provided 50-60% protection throughout the period of observation (14 months). Neither vaccine caused any serious side effects. A controlled field trial of the effectiveness of various doses of cholera El Tor vaccine was organized in Negros Occidental Province, an area of endemic cholera in the Philippines, in 1966 and 1967, on 359 600 volunteers. The population was divided, by random allocation, into four equal groups, and vaccines were administered as follows: Group A, one dose of 1 ml of vaccine containing 8 x 10(9) organisms/ml; Group B, 2 doses (1 ml each) of the same cholera vaccine; Group C, one dose of vaccine containing 16 x 10(9) organisms/ml; and Group D, 2 doses of typhoid vaccine as a control.During the follow-up period of 6 months, a total of 95 bacteriologically proven cases were observed. The rates of protection were 53%, 55% and 58% respectively, which were statistically significant. Maximum protection was observed in Group C, but the difference between the degree of protection in the various groups was not statistically significant. In view of the encouraging laboratory findings on the efficacy of intradermal administration of cholera vaccination in small doses, a controlled field trial was undertaken in the Philippines to evaluate the efficacy of the two routes for cholera vaccination. The trial has shown that these routes are effective, both giving a significant degree of protection against cholera. However, the vaccine afforded longer-lasting protection when administered subcutaneously (6 months) than when given intradermally (4 months), and was significantly more effective in children in the 1-5-year age group in this endemic area. nan Monovalent Ogawa and Inaba vaccines prepared from classical and El Tor strains of Vibrio cholerae were field-tested in Negros Occidental, Philippines, where cholera El Tor, serotype Ogawa, is endemic. The monovalent classical Ogawa and Inaba vaccines were of the same lots as those tested in East Pakistan in 1968-69. The results indicated that all four types of vaccine tested offered significant degrees of protection varying from 58% to 71%. The Ogawa vaccines were slightly, though not significantly, more protective than the Inaba vaccines against disease caused by Ogawa. The biotypes of the vaccine strains were found to be of no consequence. To assess the effectiveness of cholera vaccines, 2 controlled field trials were made in Calcutta-an endemic area-during 1964 and 1965. Three Indian vaccines of which 1 was grown on casein hydrolysate and 2 on agar, a freeze-dried vaccine from the Walter Reed Army Institute of Research (WRAIR), Washington, D.C., and an El Tor vaccine from the Philippines were used, with typhoid-paratyphoid (TAB) vaccine as a control. The 210 112 volunteers were vaccinated subcutaneously with a single dose of one of the vaccines.In the 1964 trial, the number of bacteriologically confirmed cases was not enough to show statistically significant differences in incidence between the 5 vaccine groups and the control group. However, the WRAIR freeze-dried vaccine protected about 40% of the vaccinees for 6 months after vaccination, although the efficacy was higher (57%) during the first 3 months than during the subsequent 3 months (28%). Agar-grown vaccine, produced by the Central Research Institute, Kasauli, was 37% efficacious.In the 1965 trial, owing to the small number of cases in the study area, the Kasauli vaccine was the only one to show statistically significant protection (40%). A controlled field trial to determine the efficacy of a single dose of an aluminium phosphate-adsorbed cholera vaccine was conducted in Calcutta during 1975-77. An aluminium phosphate-adsorbed tetanus toxoid was used as the placebo. Follow-up of the immunized volunteers for a period of two years showed that the adsorbed cholera vaccine provided 100% protection to children under five years of age for 6 months, 88.9% for 12 months, and 91.7% for 18 months (P<0.05). The overall protection for all age groups was 58.5% for 18 months. There were no serious side effects following the anti-cholera inoculations. nan A cholera-vaccine field trial in a rural area of East Pakistan where cholera is highly endemic has indicated that a high-potency whole-cell vaccine can provide significant protection against disease due to Vibrio cholerae for at least 18 months. This vaccine gave more than 70% protection during the first cholera season after vaccination. In the second cholera season after the administration of a single dose of vaccine, protection fell in those under 5 years of age, while continuing at significantly effective levels in older persons.Purified Ogawa antigen (lipopolysaccharide) afforded significant protection to adults against disease due to the heterologous Inaba serotype, but only protected children against milder diarrhoeas.The effect of cholera vaccine on the incidence of infections among family contacts of cholera patients was variable. Vaccine had no effect on the proportion of asymptomatic infections.Diarrhoeal disease associated with V. cholerae occurred predominantly among children, while protection was most marked among adults. Adverse reactions were practically restricted to the adults, suggesting that children will not only tolerate a larger dose, but actually require a larger dose for maximum protection against infection. This article presents the results of a comparative study of the reactogenicity and the serological response induced by a number of cholera vaccines. Conducted in the USSR on 998 adults aged 18 years and over, the study covered whole-cell heat-killed and formalin-inactivated cholera vaccines, whole-cell heat-killed El Tor vaccine, and a new partially purified toxoid preparation proposed for the immunoprophylaxis of cholera-all administered by hypodermic syringe or jet injector. The most marked reactions were found to occur with the formalin-inactivated cholera vaccine and the least marked with the partially purified toxoid. It was also established that the toxoid was no less effective than the whole-cell vaccine in inducing the intense production of antibodies to the Inaba serotype and, in somewhat lesser degree, to the Ogawa serotype of the El Tor vibrio. It was the only preparation to give rise to intense production of specific antitoxins in 95-98% of cases. The reactions to and immunogenic properties of the cholera vaccines did not show any statistically significant difference whether administered by hypodermic syringe or by jet injector. In a controlled study, it has been shown that the prior administration of cholera vaccine had no beneficial effect on the clinical course of cholera as measured by either the condition of the patient on admission to hospital or the subsequent course of the disease. In fact, the disease was, if anything, more severe in those who had received cholera vaccine. Although the presence of a high vibriocidal titre is associated with protection from cholera, pre-existing antibody had no effect on the clinical course of the disease in those patients who developed cholera. In a controlled field trial on some 584 000 people in an endemic cholera El Tor area in the Philippines, it was demonstrated that cholera vaccines gave moderate protection of short duration. Injection of a single dose of vaccine prepared from either Vibrio cholerae or Vibrio El Tor gave over 50% protection for the first two months. The immunity conferred by the V. cholerae vaccine rapidly declined after three to four months. The V. El Tor vaccine gave protection for six months, but its effectiveness declined. An oil-adjuvant vaccine prepared from V. cholerae conferred an increasing degree of protection of long duration, but, owing to severe vaccination reactions, its use could not be recommended.
Injected cholera vaccines appear to be safe and relatively more effective than usually realized. Protection against cholera persists for up to two years following a single dose of vaccine, and for three years with an annual booster. However, they have been superseded by oral vaccines.