Serological studies on cholera patients and their household contacts in Calcutta in 1968

Vibriocidal and agglutination tests have been performed, using a microtechnique, on 170 pairs of sera obtained, at intervals of 13-26 days, from bacteriologically proven cholera patients and their contacts, carriers and vibrio-negative contacts. Of the carriers, 44%-46% of those with low initial vibriocidin titres (≤ 1:80) and 28%-37% of those having high initial titres (≤ 1:160) showed a 4-fold or greater rise in vibriocidal titres. Carriers and negative contacts exhibited almost similar pictures. With an increase in the number of carriers per household, a larger number of negative contacts developed significant titres in their second samples. In general, initial titres increased with age, but were highest in the 10-25-years age-group: however, 30% of children below 10 years of age had titres ≥ 1:640. The results indicated that individuals with high titres might become carriers but may not suffer from overt cholera.     

Report of the 1966-67 cholera vaccine field trial in rural East Pakistan. 2. Results of the serological surveys in the study population--the relationship of case rate to antibody titre and an estimate of the inapparent infection rate with Vibrio cholerae

The 1966-67 cholera vaccine field trials in East Pakistan tested 1- and 2-dose schedules of a commercial cholera vaccine in 40 000 children aged 3 months to 14 years. Randomsample serological surveys, made prior to the inoculations and 3 months and 6 months after the inoculations, demonstrated that there was a rise in the vibriocidal titres of the vaccinated children during the first 3 months after inoculation and a subsequent fall by the end of the second 3 months. The antibody response to 2 doses of cholera vaccine was better than the response to a single dose in children under 5 years of age. In children aged 5-14 years, the antibody response was similar for both inoculation schedules. Since the majority of the older children had vibriocidal antibodies before inoculation, the data suggest that the single dose acted as a booster, and this effect was not enhanced by a second inoculation.     

A serological survey for cholera antibodies in rural East Pakistan: 1. The distribution of antibody in the control population of a cholera-vaccine field-trial area and the relation of antibody titre to the pattern of endemic cholera*

Controlled cholera vaccine field trials were held in Matlab Bazar in rural East Pakistan in 1963 and 1964. In July—September 1965, a serological survey for cholera antibodies was carried out on a random sample of the field-trial population. Results are given for the control group only, as representative of the pattern found in an endemic cholera area. Only 2% of the blood samples from children under 10 years of age were found to have detectable agglutinating antibody (titres of 1:20 or more), while the proportion in the age-group over 30 years was 27%-30%. Tests for vibriocidal antibody showed that none of the blood samples from children under 1 year of age contained detectable antibody, while 87%-90% of those from adults over 30 years did so. The rise in the geometric mean vibriocidal titre showed an almost linear correlation with a sharp fall in the cholera case rate with age. Since a similar survey in a non-endemic area (Czechoslovakia) did not reveal any rise in antibody titre with age, and since cholera epidemics in areas without recent experience of the disease are characterized by a higher incidence rate in adults than in children, it is suggested that the antibody titres give a measure of the level of immunity in a population.     

The immune response of guinea pigs and buffalo calves to the locally prepared Brucella abortus strain 19 vaccine

Brucella abortus vaccine was prepared from strain 19 imported from Germany. The vaccine induced a good immune response in guinea pigs as evidenced by a serological titre of 328 international units (IU)/ml 10 days post-vaccination. Vaccinated guinea pigs also withstood an experimental challenge of 5,000 colony-forming units of a locally isolated virulent B. abortus strain. This vaccine, containing 7 x 10(10) viable organisms, induced a significant immune response in 8 to 10.5 month old female buffalo calves. Significant serum agglutination test (SAT) titres were seen on day 7 following vaccination. The highest SAT titres were observed on day 14 post-vaccination and the titres started declining thereafter. The rate of decrease was slow from day 14 to day 49 post-vaccination; however, a rapid decrease in titres was seen from day 49 to day 91 post-vaccination. Negligible SAT titres were observed on day 91 post-vaccination. Specific immunoglobulin G titres, as measured by 2-mercaptoethanol treated SAT, also followed a similar trend and the titre of all five of the calves that were vaccinated became zero on day 91 post-vaccination.     

Long-term persistence of anti-HBs after vaccination with a recombinant DNA yeast-derived hepatitis B vaccine: 8-year results

The aim of this study was to evaluate the persistence of antibodies 7 years after hepatitis B booster administration in healthy adult volunteers who were vaccinated in 1987. In October 1986, 188 seronegative, healthy adult volunteers (117 men and 71 women) were vaccinated with a 20 μg dose recombinant DNA yeast-derived hepatitis B vaccine. Mean age of the study group was 23.3 years (±0.28). Immunisation was carried out according to a 0-1-2 month vaccination schedule, with a boosterdose at 12 months. Of the 159 subjects who received the full vaccination course, 63 (40%) had a blood sample taken 8 years after the first vaccination. Of these 63 subjects, five were excluded from teh analysis due to an irregular vaccination schedule and four subjects did not complete the accompanying questionnaire on possible booster administration. So, 54 subjects remained available for further analysis. Fourteen individuals had received an additional booster of hepatitis B vaccine sometime between 1989 and 1994. The geometric mean titre (GMT) at month 13 for these 14 individuals was 1494 mIU ml⁻¹, compared with 3103 mIU ml⁻¹ for those who did not receive an interim booster. Forty subjects, who received no additional booster dose besides that of month 12, met the inclusion criteria of the follow-up study. Of these, all subjects except one were seropositive for anti-HBs at month 96 (GMT: 215.9 mIU ml⁻¹). All subjects were still anti-HBc negative at that time. Distribution of individual antibody titres revealed that overall 92.5% of subjects retained protective antibody levels (10 mIU ml⁻¹); 72.5% of vaccinees retained high levels of anti-HBs (100 mIU ml⁻¹) as compared to 99.2 and 97.0% at month 13, respectively. A positive correlation was found between the subjects' titres at month 13 and month 96. A 0-1-2 dose vaccination course with a booster dose administered at month 12, induces a protective immune response which lasts at least until 7 years after the full vaccination course of the subjects. A positive correlation was found between the anti-HBs antibody titres at month 13 and month 96.     

A serological survey for cholera antibodies in rural east Pakistan. 2. A comparison of antibody titres in the innunized and control populationd of a cholera-vaccine field-trial area and the relation of antibody titre to cholera case rate

Controlled field trials of a highly antigenic cholera vaccine were held in Matlab Bazar in rural East Pakistan in 1963 and again in 1964. In July—September 1965, a serological survey for cholera antibodies was carried out on a random sample of the field-trial population. This survey revealed that it was possible to demonstrate the effect of a single injection of the cholera vaccine per head on the proportion of the population with detectable vibriocidal and agglutinating antibody 10 and 22 months after injection. More significantly, the reduction in cholera case rate caused by the vaccine could be correlated with the rise in vibriocidal antibody after vaccination, suggesting that the serological response to vaccine in man may be a useful measure of vaccine potency. The survey also indicated that in this endemic cholera area, with a high level of immunity in adults, a single injection of cholera vaccine was in fact a booster dose for the majority of the population. Thus, the results of cholera vaccine field trials in endemic areas cannot be directly extrapolated to predict the effects of the same vaccine in non-endemic areas.     

Antibody responses in humans to an inactivated hantavirus vaccine (Hantavax).

Hantaviruses cause haemorrhagic fever with renal syndrome (HFRS) and result in severe human morbidity and mortality. Safe and effective vaccines are needed urgently in order to reduce the incidence of human illness. Hitherto studies of hantavirus vaccine efficiency have been limited to individuals at low risk of infection. In this study the immune response to an inactivated hantavirus vaccine was measured in 64 human volunteers at high risk of infection by virtue of residence and occupation. 30 d after vaccination, 79% of subjects developed a significant hantavirus antibody titre as measured by immunofluorescence (IFA) and 62% by enzyme linked immunosorbent assay (ELISA). Seroconversion rates increased to 97% one month after the booster dose. Neutralising antibody titres paralleled this trend with 13% of vaccine recipients producing neutralising antibody one month after the first dose and 75% of vaccine recipients responding one month after boosting. Antibody titres had declined by one year, however, with only 37% and 43% of sera positive by IFA and ELISA, respectively. Re-vaccination at this time produced a vigorous anamnestic response with 94% and 100% of vaccine recipients yielding positive antibody titres. Only 50% of the sampled population, however, produced neutralising antibodies following the booster dose one year later. The vaccine was well tolerated and there were no apparent differences in the responses of males and females. However, further improvement of this vaccine is necessary in order to induce a more longlasting humoral immune response.     

Suppressive effect of zinc on antibody response to cholera toxin in children given the killed, B subunit-whole cell, oral cholera vaccine

In a previous study, children aged 2-5 years old in Bangladesh were supplemented orally with a single dose of Vitamin A (200,000 IU) and a placebo for zinc (zinc equivalent to 20 mg of elemental zinc) everyday for 42 days (group A), zinc and a placebo for Vitamin A (group Z), zinc and Vitamin A (group AZ) or both placebos (group P). All children were orally immunised with two doses of the killed cholera vaccine containing whole cells and a recombinant B subunit of cholera toxin (CT). The number of children who responded with > or = 4-fold vibriocidal antibody (a proxy indicator of protection against cholera) was significantly greater among the zinc-supplemented groups than among the non-zinc-supplemented groups, while Vitamin A supplementation did not appear to have any effect. The sera from these children were assayed for antibody to CT. Antibody to CT is known to exert a synergistic protective effect against cholera in animal studies, and offer significantly higher short-term protection against cholera and significant short-term protection against enterotoxigenic Escherichia coli diarrhoea in humans on oral immunisation with the cholera vaccine. Children who received zinc had significantly reduced levels of serum antibodies to CT than children who received placebos only. Factorial analysis showed a trend for zinc showing a reduction in the number of children responding with CT-antibody, while Vitamin A did not appear to have any effect. Thus, zinc enhanced vibriocidal antibody response, but suppressed CT-antibody response, suggesting that zinc supplementation has different modulating effects on vibriocidal antibody response and CT-antibody response.     

Booster vaccination in the elderly: their success depends on the vaccine type applied earlier in life as well as on pre-vaccination antibody titers

BACKGROUND: Recent retrospective studies demonstrate that elderly persons have a shortened protection period following vaccination with recall antigens. METHODS: We now analysed the effect of booster vaccination with a multivalent vaccine containing tetanus, dipththeria, pertussis and polio antigens in 252 healthy elderly persons. The magnitude of the humoral immune response was assessed by antibody measurements. RESULTS: Comparison with a small control group of 21 younger persons demonstrates that pre- and post-vaccination antibody concentrations are lower in elderly persons for all antigens except polio, for which higher pre- and similar post-vaccination antibody levels are observed. Using multiple linear regression analysis we also show that the magnitude of the humoral immune response in elderly persons greatly depends on pre-vaccination antibody concentrations in the case of tetanus, diphtheria and pertussis, but much less so in the case of polio, against which priming and preceding booster immunizations were performed with attenuated live vaccine. CONCLUSION: Regular booster vaccinations throughout life are of clinical importance to maintain the ability to respond to recall antigens in old age. Longer lasting protection and good responsiveness to boosting in spite of low antibody titres can be expected following exposure to live vaccine earlier in life.     

Preparation and laboratory testing of plain and aluminum hydroxide-adsorbed cholera vaccines used in a field trial in Indonesia.

Two types of cholera vaccine were prepared: a plain vaccine and an aluminium hydroxide-adsorbed vaccine, by using the Inaba NIH 35A3 and Ogawa NIH 41 serotypes of Vibrio cholerae. For cultivation, a solid medium was used and the cultures were inactivated with 0.02% thiomersal and by heating for 1 hour at 56°C. The final vibrio concentration of the vaccines was adjusted to 16 × 10⁹ vibrios/ml (equal proportions of the two serotypes). The antigenicity of the vaccines was assessed by the active mouse protection test and by the antibody production test, i.e. by determinating the vibriocidal antibodies in the sera of immunized mice. The results of the active mouse protection test showed that the antigenicity of the Inaba and Ogawa components of both vaccines met the WHO Requirements. The antigenicity of the Inaba component of both vaccines was about the same. The antigenicity of the Ogawa component of the plain vaccine appeared to be somewhat higher than that of the adsorbed vaccine. In the antibody production test, the adsorbed vaccine elicited a higher and longer-lasting immune response than the plain vaccine.     

Randomized double-blind placebo controlled trial to evaluate the safety and immunogenicity of the live oral cholera vaccine strain CVD 103-HgR in Swiss adults

A randomized, double-blind, placebo controlled trial was conducted in 50 healthy Swiss adults to assess the safety and immunogenicity of the live oral attenuated cholera vaccine candidate strain Vibrio cholerae CVD 103-HgR (classical, Inaba). A single dose of 5 × 10⁸ viable CVD 103-HgR organisms, administered in a buffered liquid formulation, was well tolerated as compared with individuals who received an equivalent amount of heat-killed Escherichia coli K-12 placebo. Eighty-eight percent of subjects receiving CVD 103-HgR mounted a significant (>fourfold) rise in Inaba vibriocidal titre while 68% did so for the heterologous Ogawa serotype. The magnitude of the vibriocidal antibody response (as measured by peak geometric mean titre and by fold-rise in titre over baseline) was greater for the homologous Inaba serotype. Nineteen out of 25 volunteers (76%) responded with a significant (p < 0.05) rise in serum antitoxin levels. No vaccine who received the E. coli K-12 placebo mounted a significant rise in either vibriocidal or antitoxin antibody levels. These results corrobrate the safety and immunogenicity of CVD 103-HgR in healthy adult volunteers.     

Highly pathogenic avian influenza (H7N7): vaccination of zoo birds and transmission to non-poultry species

In 2003 an outbreak of highly pathogenic avian influenza virus (H7N7) struck poultry in The Netherlands. A European Commission directive made vaccination of valuable species in zoo collections possible under strict conditions. We determined pre- and post-vaccination antibody titres in 211 birds by haemagglutination inhibition test as a measure of vaccine efficacy. After booster vaccination, 81.5% of vaccinated birds developed a titre of ≥40, while overall geometric mean titre (GMT) was 190 (95% CI: 144–251). Birds of the orders Anseriformes, Galliformes and Phoenicopteriformes showed higher GMT, and larger percentages developed titres ≥40 than those of the other orders. Antibody response decreased with increasing mean body weight in birds ≥1.5 kg body weight. In the vicinity of the outbreak, H7N7 was detected by RT-PCR in wild species (mallards and mute swans) kept in captivity together with infected poultry, illustrating the potential threat of transmission from poultry into other avian species, and the importance of protecting valuable avian species by means of vaccination.     

Characterization of antibody responses to annual influenza vaccination over four years in a healthy elderly population

The effects of yearly influenza immunization on the level of antibody responses were assessed in 92 healthy elderly subjects immunized over four contiguous years (1993–1996) with a trivalent influenza vaccine that included A/Texas annually. Anti-A/Texas antibodies increased significantly and similarly post-vaccination each year, but returned to comparable baseline levels annually. Percentages of subjects with anti-A/Texas titers ≥40 post-vaccination were comparable over four years. Importantly, post-vaccination titers ≥40 to A/Texas in 1993–1994 predicted anti-A/Texas titers ≥40 in subsequent years. Thirty percent of individuals produced four-fold rises to any vaccine component the first year it was included in the vaccine, however, this percentage decreased to about 10% after subsequent vaccination with the same component. This study clearly supports the concept that annual immunization with the same influenza vaccine component over multiple years does not significantly decrease antibody titers in a healthy elderly population.     

Response to 2009 pandemic and seasonal influenza vaccines co-administered to HIV-infected and HIV-uninfected former drug users living in a rehabilitation community in Italy

Background

2009 A(H1N1) pandemic influenza vaccination was recommended as a priority to essential workers and high-risk individuals, including HIV-infected patients and people living in communities.

Methods

HIV-infected and HIV-uninfected former drug-users (18-60 years old) living in a rehabilitation community (San Patrignano, Italy) received one dose of a MF59-adjuvanted 2009 pandemic influenza vaccine and one dose of a 2009-2010 seasonal trivalent inactivated influenza vaccine (containing A/Brisbane/59/2007(H1N1), A/Brisbane/10/2007(H3N2), B/Brisbane/60/2008) simultaneously. Antibodies against each vaccine antigen were determined at the time of vaccination and one and six months post-vaccination by hemagglutination-inhibition test.

Results

49 HIV-infected and 60 HIV-uninfected subjects completed the study. Most (98%) HIV-infected participants were on antiretroviral treatment, the median CD4+ cell count was 350 (IQR 300) cells/μl and viremia was suppressed in 91.8% of cases. One month post-vaccination, no significant changes in immune-virological parameters were observed. One month post-vaccination, the immune responses to both pandemic and seasonal vaccine met the EMA-CPMP criteria for immunogenicity of influenza vaccines in both HIV-infected and HIV-uninfected subjects. No difference in vaccine responses was observed between the two groups. Six months after vaccination, the percentages of vaccinees with antibody titres ≥1:40 and antibody geometric mean titres significantly decreased in both groups. However, they were significantly lower in HIV-infected than in HIV-uninfected vaccinees. In subjects who had been primed to seasonal influenza the year before (through either vaccination or natural infection), levels of antibodies against 2009 A(H1N1) were higher than those measured in unprimed subjects, both one month and six months post-vaccination.

Conclusions

The co-administration of a single dose of 2009 pandemic MF59-adjuvanted influenza vaccine with a seasonal vaccine provided a protective immune response in both HIV-infected and HIV-uninfected individuals. Subjects who had been primed to seasonal influenza in the year preceding the pandemic had a more vigorous and long-lasting antibody response to 2009 pandemic vaccine.     

Effect of sequence variation in meningococcal PorA outer membrane protein on the effectiveness of a hexavalent PorA outer membrane vesicle vaccine in toddlers and school children

Though meningococcal conjugate vaccines are effective against serogroup C, there is currently no vaccine solution for serogroup B disease. PorA outer membrane protein (OMP) is a potential serogroup B vaccine candidate. A hexavalent PorA outer membrane vesicle (OMV) vaccine has been evaluated in phase I and II trials with promising results. However, considerable sequence variation occurs in the variable regions (VRs) encoding these serosubtypes. By using five wild type P1.19,15 variant strains we examined the serum bactericidal antibody (SBA) titres from sera collected from toddlers and school children pre- and post-vaccination. The numbers of subjects with SBA titres of <4, 4 and > or = 8 varied greatly between the different strains. This was also reflected when > or = 4-fold rises in SBA titres were examined. This finding in sera from toddlers and school children may have implications for PorA based vaccines.     

Report of the 1966-67 cholera vaccine trial in rural East Pakistan

A controlled cholera vaccine field trial was carried out in rural East Pakistan to determine the efficacy of a cholera vaccine of average antigenic potency when used in a continuing programme with annual reimmunizations. A cohort of 40 000 children aged 0-14 years was equally divided into a control group and 3 vaccine groups. Inoculations of vaccine were given annually for 3 years just before the start of the cholera season, and follow-up continued for 2 additional years. The results indicate that there was increasing protection with reimmunization, reaching a maximum with 3 doses. One dose produced 43% protection, 2 doses 64%, 3 doses 81%, and 4 doses 76%. Protection was more sustained after reimmunization; being 50% and 39%, 1 and 2 years after the fourth injection, respectively. Serological surveys suggested a general parallel in the antibody response to vaccine and the level of protection achieved; however, the levels of vibriocidal antibody titres could not be related directly to levels of protection. The overall protection achieved with the 3-year programme of annual reimmunizations was 55% for the group receiving one inoculation annually, and 65% for the group receiving 2 inoculations in the first year followed by annual reimmunizations. When the costs and effectiveness of annual vaccine programmes are compared with those for cholera treatment centres, it becomes clear that the cholera vaccines now available are not appropriate alternatives to treatment in routine cholera control programmes.     

The relationship of vibriocidal antibody titre to susceptibility to cholera in family contacts of cholera patients

A bacteriological and serological study of family contacts of 81 cholera patients was carried out in Dacca, East Pakistan. In the 10-day follow-up, 78 (16.7%) of 466 contacts were found to be infected with Vibrio cholerae; half of them were symptomatic and 29 had to be admitted to hospital. A study of serum pairs revealed a 4-fold, or greater, rise in titre in 86% of those infected in whom diarrhoea was present, and in 77% of individuals with inapparent infections. The infection rate fell markedly with age. Serological tests for vibriocidal antibody on blood specimens collected at the initiation of the follow-up revealed higher titres with increasing age. Vibrio cholerae infection, whether symptomatic or asymptomatic, predominantly occurred in individuals with low titres.     

Investigations into the safety and immunogenicity of a killed oral cholera vaccine developed in Viet Nam

OBJECTIVE: To evaluate a killed oral cholera vaccine produced in Viet Nam, and to compare the Vietnamese vaccine with one that is licensed internationally. METHOD: Two-dose regimens of a locally produced, bivalent, anti-O1, anti-O139 killed oral whole-cell cholera vaccine (biv-WC) and of a commercially available, monovalent (anti-O1) oral recombinant B subunit-killed whole-cell cholera vaccine (rBS-WC) were compared in two trials in Viet Nam. In the first trial, 144 adults were randomized to biv-WC with or without buffer, rBS-WC with buffer, or placebo without buffer. In the second, 103 children aged 1-12 years were randomized to biv-WC without buffer, rBS-WC with buffer, or placebo without buffer. FINDINGS: No regimen was associated with significant side-effects. In adults, ca 60% of recipients of either vaccine exhibited at least fourfold serum anti-O1 vibriocidal antibody responses and ca 40% of recipients of biv-WC demonstrated anti-O139 vibriocidal responses. Both anti-O1 (ca 90% in each vaccine groupand anti-O139 (68% in the biv-WC group) vibriocidal responses occurred more frequently in children. The responses to biv-WC were unaffected by the receipt of buffer. CONCLUSION: It was concluded that biv-WC was safe and immunogenic, that it could be administered without buffer, and that it could elicit robust immune responses even in children, for whom the risk of endemic cholera is highest.     

Randomized,double-blind,placebo-controlled trial to evaluate the safety and immunogenicity of live oral cholera vaccine 638 in Cuban adults

A randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the safety, reactogenicity and the immunogenicity of a 2 × 10⁹ CFU dose of the 638 lyophilized live attenuated cholera vaccine for oral administration, formulated and produced at Finlay Institute, City of Havana, Cuba. Thirty-six healthy female and male adult volunteers from 18 to 40 years old were involved, clinically examined and laboratory tested after the informed consent signature. Adverse events were monitored and seroconversion rates and geometrical mean titer (GMT) of vibriocidal antibodies were tested in volunteer's sera samples. Neither serious adverse events nor other damages to the volunteers due to vaccine or placebo feeding were reported during the clinical follow-up period of this study; none of the adverse events registered within the first 72 h after inoculation were life-threatening for volunteers. Neither severe nor moderate adverse events were reported. Sixty-one percent of subjects showed mild expected adverse events in an interval lower than 24 h up to the first 72 h, 75% of these in the vaccinated group and 18% in the placebo group. Fourteen days after inoculation the GMT of vibriocidal antibodies in the vaccine group significantly increased in comparison to the placebo group. All subjects in the vaccine group (24) seroconverted (100%). Results show that this vaccine is safe, well tolerated and immunogenic in healthy female and male volunteers.     

Immunogenicity and safety of a hexavalent meningococcal outer-membrane-vesicle vaccine in children of 2-3 and 7-8 years of age

To study the reactogenicity and immunogenicity of a hexavalent meningococcal outer-membrane-vesicle vaccine (OMV), two different dosages of this vaccine (7.5 and 15 microg of individual PorA proteins) consisting of vesicles expressing class 1 outer-membrane proteins (OMPs) of subtypes P1.7,16; P1.5,2; P1.19,15 and P1.5(c), 10; P1.12,13; P1.7(h),4 were administered to a group of 7-8 year (n=165) and a group of 2-3 year old children (n=172). Control groups of children with similar ages were vaccinated against hepatitis B. All participants received three injections. Pre- and postimmunisation sera were tested for bactericidal antibodies against six isogenic meningococcal vaccine strains expressing different PorA proteins. Antibody titres against OMP of the two different vesicles (PL16215 and PL10124) were measured by ELISA. The meningococcal hexavalent OMV vaccine was well tolerated. No statistically significant differences were seen between the high and low dose of hexavalent meningococcal OMV vaccine. The percentage of children showing a fourfold increase of bactericidal antibody titres against the specific serosubtype varied in toddlers from 28 to 98% and in older children from 16 to 100%. Both ELISA antibody titres and bactericidal activity showed the highest level in the youngest age-group.