Molecular design of cholera vaccines

Cholera is still a serious public health problem in developing countries, particularly those in tropical regions. This has stimulated considerable research into the molecular analysis of pathogenesis resulting in the identification of a number of critical components required for both colonization of the gut mucosa and the disease symptoms. These components are the targets for rational molecular approaches to vaccine development.     

Protective activity of cholera vaccines against E1 Tor cholera vibrios

With the advent of epidemic El Tor cholera there has been concern about the value of cholera vaccine prepared from classical cholera strains.     

Adjuvant effect of DEAE-dextran on cholera vaccines

Investigations into the effectiveness of DEAE-dextran as an adjuvant of whole cell cholera vaccines (Vibrio cholerae Inaba and Ogawa serotypes) were conducted using two methods: (a) the active mouse protection test, (b) the determination of antibody production in the sera of immunized mice by measuring the level of vibriocidal antibodies, and by an enzyme-linked immunosorbent assay (ELISA). In all tests, the DEAE-dextran-adjuvanted vaccine showed an antigenicity substantially superior to that achieved without adjuvants.     

The state-of-the-art of approved and under-development cholera vaccines

Cholera remains a huge public health problem. Although in 1894, the first cholera vaccination was reported, an ideal vaccine that meets all the requirements of the WHO has not yet been produced. Among the different approaches used for cholera vaccination, attenuated vaccines represent a major category; these vaccines are beneficial in being able to induce a strong protective response after a single administration. However, they have possible negative effects on immunocompromised patient populations. Both the licensed CVD103-HgR and other vaccine approaches under development are detailed in this article, such as the Vibrio cholerae 638 vaccine candidate, Peru-15 or CholeraGarde^® and the VA1.3, VA1.4, IEM 108 VCUSM2 and CVD 112 vaccine candidates. In another strategy, killed V. cholerae vaccines have been developed, including Dukoral^®, mORCAX^® and Sanchol™. The killed vaccines are already sold, and they have successfully demonstrated their potential to protect populations in endemic areas or after natural disasters. However, these vaccines do not fulfill all the requirements of the WHO because they fail to confer long-term protection, are not suitable for children under two years, require more than a single dose and require a distribution chain with cold storage. Lastly, other vaccine strategies under development are summarized in this review. Among these strategies, vaccine candidates based on alternative drug delivery systems that have been reported lately in the literature are discussed, such as microparticles, proteoliposomes, LPS subunits, DNA vaccines and rice seeds containing toxin subunits. Preliminary results reported by many groups working on alternative delivery systems for cholera vaccines demonstrate the importance of new technologies in addressing old problems such as cholera. Although a fully ideal vaccine has not yet been designed, promising steps have been reported in the literature resulting in hope for the fight against cholera.     

Private demand for cholera vaccines in Beira, Mozambique

In the summer of 2005, we interviewed 996 randomly selected respondents in Beira, Mozambique concerning their willingness and ability to pay for cholera vaccine for themselves and for other household members. Respondents were told that two doses of the vaccine would be required 2 weeks apart, and that the cholera vaccine would offer excellent protection against infection for the first year following vaccination, and some protection during the second and third year after a person is vaccinated. This research was carried out in order to learn more about private demand for vaccines in a cholera-endemic area. We asked two types of valuation questions: (1) a discrete-price offer for a vaccine that could be purchased for household members and (2) a payment card designed to assess uncertainty in the respondent's demand for a vaccine for self-protection. We estimate average household willingness to pay (WTP) for cholera vaccines in Beira to be 2005 US$ 8.45. This estimate of household WTP represents the perceived private economic benefits to a household--six persons on average--of giving all members free cholera vaccines.     

Controlled field trial of the effectiveness of cholera and cholera El Tor vaccines in Calcutta

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.     

New vaccines

New technology is allowing the development of more effective and safer vaccines to replace old vaccines and provide protection against a wider range of diseases. The worldwide priority, however, must be to increase the uptake of existing vaccines to reduce childhood mortality and morbidity.     

Post-licensure deployment of oral cholera vaccines: a systematic review

Objective

To describe and analyse the characteristics of oral cholera vaccination campaigns; including location, target population, logistics, vaccine coverage and delivery costs.

Methods

We searched PubMed, the World Health Organization (WHO) website and the Cochrane database with no date or language restrictions. We contacted public health personnel, experts in the field and in ministries of health and did targeted web searches.

Findings

A total of 33 documents were included in the analysis. One country, Viet Nam, incorporates oral cholera vaccination into its public health programme and has administered approximately 10.9 million vaccine doses between 1997 and 2012. In addition, over 3 million doses of the two WHO pre-qualified oral cholera vaccines have been administered in more than 16 campaigns around the world between 1997 and 2014. These campaigns have either been pre-emptive or reactive and have taken place under diverse conditions, such as in refugee camps or natural disasters. Estimated two-dose coverage ranged from 46 to 88% of the target population. Approximate delivery cost per fully immunized person ranged from 0.11–3.99 United States dollars.

Conclusion

Experience with oral cholera vaccination campaigns continues to increase. Public health officials may draw on this experience and conduct oral cholera vaccination campaigns more frequently.     

A controlled field trial of the effectiveness of cholera and cholera El Tor vaccines in the Philippines

A controlled field trial on some 584 000 people in an endemic cholera El Tor area in the Philippines demonstrated that cholera vaccines gave moderate protection of short duration. Injection of a single dose of vaccine prepared from either Vibrio cholerae or El Tor vibrios gave over 50% protection for the first 2 months. The immunity conferred by the V. cholerae vaccine declined rapidly after 3 to 4 months. The effectiveness of the El Tor vaccine continued for 6 months. An oil-adjuvant vaccine prepared from V. cholerae conferred an equally high degree of protection for a longer period of time, but, owing to severe vaccination reactions, its use could not be recommended.     

Immunogenicity of two formulations of oral cholera vaccines in Thai volunteers

A formulation of oral vaccine consisting of Vibrio cholerae lipopolysaccharides (LPS), cell-bound haemagglutinin (CHA) and procholeragenoid (P), namely vaccine A, was compared with another formulation, vaccine B, prepared from killed whole vibrios plus procholeragenoid on their immunogenicity and reactogenicity in Thai male volunteers. Volunteers were randomly allocated into three groups. The first two groups received orally three doses of vaccines A and B, respectively at 14-day intervals. Volunteers in group 3 were controls and received orally 100 ml 5% (w/v) NaHCO3 also at 14-day intervals. Serum samples were collected from all volunteers before each immunization. Intestinal lavage was performed 3 to 7 days before the first dose of vaccine or placebo and 7, 21 and 45 days after the last dose. Serum vibriocidal antibodies were determined and class-specific, antigen-specific antibodies of all serum and lavage samples were assessed by indirect enzyme-linked immunosorbent assay (ELISA) using purified LPS, CHA and cholera toxin (CT) as antigens. Diarrhoea occurred in 10 and 40% of the vaccinees ingesting the vaccines A and B, respectively. The immunogenicity of the vaccine B in terms of seroconversion for vibriocidal antibodies and anti-LPS was higher than the vaccine A. Both vaccines had equal immunogenicity concerning serum anti-CT, while the vaccine A was slightly better than the vaccine B on serum anti-CHA response. The immunogenicity of the two vaccines in evoking intestinal responses was different from the systemic one.(ABSTRACT TRUNCATED AT 250 WORDS)     

A controlled field trial of the effectiveness of cholera and cholera El Tor vaccines in the Philippines: Preliminary report

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.     

Impact of oral cholera vaccines in cholera-endemic countries: A mathematical modeling study

BackgroundImpact evaluation of vaccination programs is necessary for making decisions to introduce oral cholera vaccines (OCVs) in cholera-endemic countries.MethodsWe analyzed data to forecast the future global burden of cholera. We developed a mathematical model of cholera transmission in three countries as examples: Nigeria, Uganda, and Indonesia. After fitting the model, we evaluated the impact of OCVs delivered in four vaccination strategies varying by target age group and frequency of vaccination over the period of 2015–2030.ResultsData suggest that the global annual incidence of cholera will increase from 3 046 238 in 2015 to 3 787 385 in 2030 with the highest burden in Asia and Africa where overall population size is large and the proportion of population with access to improved sanitation facilities is low. We estimate that OCV will reduce the cumulative incidence of cholera by half in Indonesia and >80% in Nigeria and Uganda when delivered to 1+ year olds every three years at a coverage rate of 50%, although cholera may persist through higher coverage rates (i.e., >90%). The proportion of person-to-person transmission compared to water-to-person transmission is positively correlated with higher vaccination impact in all three countries.ConclusionsPeriodic OCV vaccination every three or five years can significantly reduce the global burden of cholera although cholera may persist even with high OCV coverage. Vaccination impact will likely vary depending on local epidemiological conditions including age distribution of cases and relative contribution of different transmission routes.     

Experimental evaluation of antitoxic protective effect of new cholera vaccines in mice.

Intraperitoneal immunization of mice and subsequent challenge with purified cholera toxin (CT) were employed to evaluate the anti-cholera toxin protective effect of two new oral cholera vaccines, live CVD 103-HgR and killed B subunit-whole cell (BS-WC). CVD 103-HgR vaccine demonstrated 100% protection of mice against 2.25 LD50 and 70% against 3 LD50 of CT. Mice immunized with BS-WC vaccine were protected against 2.25 and 3 LD50 of CT in 88 and 62% of cases, respectively. All three killed parenteral vaccines failed to protect against CT. We suggest this mouse system for preliminary evaluation of the antitoxic protective activity of cholera vaccines.     

Immunity in experimental cholera: effect of parenteral immunization with vaccines and toxoid

The protection conferred by parenteral cholera vaccines and cholera toxoid was determined in the rabbit ileal loop model of experimental cholera. Vibrio cholerae strains belonging to two different serotypes were employed, for immunization and challenge, to differentiate antibacterial and antitoxic immunity patterns. It was found that vaccines were protective but cholera toxoid was not, although serum antitoxin levels were high after administration of the latter. Antibacterial immunity was strictly serotype-specific, with evidence of cross-protection only between Ogawa and Inaba subtypes of serotype 1. Bivalent serotype 1 vaccines conferred protection against homologous challenge strains but immunity to Inaba infection was of shorter duration than immunity to Ogawa infection.     

Antibody response in the intestinal secretions of volunteers immunized with various cholera vaccines

The efficacy of various cholera vaccines in eliciting an intestinal antibody response was assessed in human volunteers who received oral live, oral killed, or parenteral cholera vaccines, or placebo. The intestinal immune response in terms of antibacterial and antitoxin antibodies was determined 2 and 4 weeks after immunization. By means of the mouse peritoneum opsonization assay and the infant mouse protection test, antibacterial activity could be detected in the intestinal secretions of volunteers who had been immunized either orally or by the parenteral route. Significant protective activity and duration of immunity were observed with the oral killed vaccine. The bacteriological data indicated the absence of significant intestinal colonization of the live attenuated strain after oral administration, and probably explains the observed lack of effectiveness of the oral vaccine compared with that of the killed vaccine. The predominant immunoglobulin class of intestinal antibody was found to be IgA. None of the vaccines used in the study elicited significant antitoxin activity in the intestinal secretions, as determined by the skin permeability neutralization test.     

New vaccines against hepatitis B

The high cost and limited availability of the plasma-derived hepatitis B vaccines have prevented their widespread use, especially in the less developed areas where they are needed most. Hepatitis B vaccines produced by recombinant technology seem to offer a solution to these difficulties. Studies reported up to now confirmed the safety of this vaccine. Immunogenicity studies in various population groups showed that seroconversion rates and antibody titres are comparable to plasma vaccine. In assessing the efficacy of the vaccine, information concerning the quality of the anti-HBs induced should complement these data. Potential live vaccines using recombinant vaccinia viruses have been constructed for hepatitis .B. Preliminary studies in rabbits and chimpanzees indicated the feasibility of future using a recombinant vaccinia virus.Chemically synthesized polypeptides corresponding to relevant epitopes of HBsAg may be useful as synthetic vaccines offering the advantages of a cheap viral immunogen free from irrelevant antigenic determinants.Finally preliminary studies for an idiotypic vaccine have already been reported.