Safety and Immunogenicity of Different Immunization Regimens of CVD 103-HgR Live Oral Cholera Vaccine in Soldiers and Civilians in Thailand

Abstract

Attenuated Vibrio cholerae oral vaccineCVD 103-HgR was welltolerated by 324 Thai soldiers and civilians. Most receiveda single 5 X 10 8 cfu dose, while 40 each receivedone or two 5 X 10 9 cfu doses. Vibriocidal antibody (the best correlate of immunity) seroconversion was lower in soldiers than civilians (P < .001). Increasing the vaccinedose to 5 X 10 9 cfu raised the geometric mean titer (P < .001). A second 5 X 10 9 cfu dose one week later did not notably increase seroconversions. Likelihood of seroconversion was inverselycorrelated with baseline vibriocidal titer (P < .001). CVD 103-HgR caused seroconversion in most subjects with baseline titers .;;1:40, including 100% of civilians after one 5 X 10 8 cfu dose, 79% of soldiers after one 5 X 10 9 cfu dose, and 45% of soldiers after one 5 X 10 8 cfu dose. In persons with elevatedbaseline titers, vibriocidal antibody seroconversion is not a sensitive measure of whether vaccine has boosted intestinal immunity; for such subjects,other measurements must be used. Study regimens in endemic areas should use a single 5 X 10 9 cfu dose.Cholera remains an important public health problem in less-developed countries, spreading readily where sanitation is compromised and often appearing in explosive epidemics. The World Health Organization has targeted the development of an improved cholera vaccine as a priority [I, 2] because the parenteral inactivated whole cell vaccine, which provides only limited, short-lived protection, can play no practical role in cholera control [3]. An ideal new cholera vaccine would be well tolerated and rapidly stimulate a high level of long-term protection among all age groups after administration ofjust one oral dose. Such a vaccine would constitute a welcome addition to the public health intervention measures available to control epidemic and endemic cholera.An important advance in immunization against cholera was documented several years ago in a field trial in BanglaReceived 6 November 1991; revised 14 January 1992. The clinical protocol followed the guidelines of the Department of Health and Human Services and was reviewed by ethical committees at the University of Maryland at Baltimore. Mahidol University. and the US Department of the Army. The studies were explained in detail, and written informed consent was obtained.Grant desh when two related inactivated oral cholera vaccines (one consisting of inactivated Vibrio cholerae 0 I organisms and the other of inactivated organisms plus the B subunit ofcholera toxin) were each shown to confer 50% protection for 3 years [4]. That experience illustrates that oral vaccines can elicit relatively long-lived protection against cholera. However, the field trial in Bangladesh also exposed notable deficiencies of those oral inactivated vaccines: Multiple, spaced doses were required to elicit protection, young children (the population with the highest incidence ofcholera in that area) were least protected, and despite administration of three spaced doses, the level of efficacy was only 50%-52% [4].With a...

Causes of Impaired Oral Vaccine Efficacy in Developing Countries

“…A reduction in vaccine immunogenicity among infants positive for rotavirus-specific IgA was recently observed during studies of Rotarix conducted in Zambia [23], Bangladesh [135] and South Africa [36], but not in India [175]. Pre-vaccination exposure seems to have a similar effect on the immunogenicity of oral cholera vaccines, including both live-attenuated [11,93,176] and inactivated vaccines [96,177,178]. Together, these findings suggest that the induc-tion of immunity following a previous encounter with a pathogen may contribute to the impaired immunogenicity of oral vaccines in high-transmission settings.…”

Safety and Immunogenicity of Single-Dose Live Oral Cholera Vaccine Strain CVD 103-HgR, Prepared from New Master and Working Cell Banks

“…However, these data from industrialized-country subjects will not be applicable for predicting the appropriate formulation and behavior of the vaccine in impoverished developing-country popula- tions. Extrapolating from the experience of previous manufacturer's formulations of CVD 103-HgR, it is expected that in developing-country populations, a one-log-higher number of organisms (i.e., ϳ5 ϫ 10 9 CFU, resembling Orochol E) will be required to achieve high rates of seroconversion of blood serum vibriocidal antibodies like those observed in industrialized-country subjects who ingested a formulation containing one-log-fewer CFU (19)(20)(21)(22)(23)(24)(25)35). Factors that modulate immunogenicity in developing-country populations and contribute to the need for a higher dosage of CVD 103-HgR have been studied extensively (19)(20)(21)(22)(23)(24)(25)35).…”

“…A single oral dose of an industrial formulation of CVD 103-HgR containing ϳ5 ϫ 10 8 CFU (subsequently commercialized as Orochol and Mutacol; Swiss Serum and Vaccine Institute, Berne, Switzerland) was well tolerated and elicited blood serum vibriocidal antibody seroconversion in ϳ92 to 97% of adult North American subjects (5,7,14,18), ϳ72 to 85% of whom also exhibited rises in blood serum IgG cholera antitoxin levels. A formulation containing ϳ5 ϫ 10 9 CFU (Orochol E) prepared for use in developing countries was shown to be well tolerated and immunogenic in diverse adult and pediatric populations (19)(20)(21)(22)(23), including in infants as young as 3 months of age (24) and in adults infected with HIV (25).…”

Human Infection withAscaris lumbricoidesIs Associated with Suppression of the Interleukin-2 Response to Recombinant Cholera Toxin B Subunit following Vaccination with the Live Oral Cholera Vaccine CVD 103-HgR

“…To investigate the potential modulatory role of ascariasis on the immune response to an orally administered vaccine in this study, we chose as a study site a rural area of Ecuador where A. lumbricoides is highly prevalent and where other small bowel-dwelling geohelminths (hookworm and S. stercoralis) are of low prevalence and used as the model oral vaccine the live attenuated oral cholera vaccine CVD 103-HgR. This vaccine, which induces strong systemic antibody responses in healthy adults (20), has been shown to be poorly immunogenic (at a dose of 5 ϫ 10 8 CFU) in populations where geohelminths are likely to be highly prevalent (31,32).…”

“…The presence of A. lumbricoides parasites in the small bowel may affect also the immune response to oral vaccines and explain the relatively poor immunogenicity of several live oral vaccines in certain populations of Asia, Africa, and Latin America compared with that seen in volunteers from industrialized countries. Such oral vaccines include Sabin oral polio vaccine (12,25), rotavirus (16,19), and the oral cholera vaccine CVD 103-HgR (31,32). Support for a potential effect of concurrent ascariasis on the response to oral vaccines is provided by a recent study that demonstrated enhanced vibriocidal antibody titers to CVD 103-HgR in ascaris-infected children pretreated with albendazole prior to vaccination (7).…”