FACTORS INFLUENCING SECONDARY VIBRIOCIDAL IMMUNE-RESPONSES - RELEVANCE FOR UNDERSTANDING IMMUNITY TO CHOLERA

Although serum vibriocidal activity is used extensively as a marker of immunity to O1 Vibrio cholerae, there are limitations in this assay t o detect instances of reexposure. We define the conditions operative i n producing secondary vibriocidal responses in North American voluntee rs primed with either wild-type V. cholerae or CVD 103-HgR live attenu ated oral cholera vaccine and then challenged with wild-type V. choler ae 1, 4, or 6 months later. Secondary serum vibriocidal responses occu rred under two distinct secondary challenge conditions. The first occu rred when secondary challenge produced a breakthrough in clinical prot ection. Following secondary exposure, 14 of 22 (64%) and 1 of 29 (3%) subjects with and without vibrio stool excretion, respectively,, had s econdary responses (P < 0.001); 5 of 6 (83%) and 10 of 45 (22%) subjec ts with or without diarrhea, respectively, mounted a secondary respons e (P = 0.006), The second condition occurred in the presence of full c linical protection but was dependent on the time interval between expo sures. No subject (0 of 17) vaccinated with CVD 103-HgR and given homo logous wild-type challenge within 4 months mounted a secondary vibrioc idal response compared with 8 of 11 (73%) vaccinated volunteers challe nged at 6 months who developed a secondary vibriocidal response (P = 0 .0009), The majority of the serum vibriocidal activity was of the immu noglobulin M (IgM) isotype, seen in 96 and 73% of subjects following p rimary and secondary exposure, respectively. Vibriocidal activity in t he IgG fraction following primary and secondary exposures occurred wit h less than or equal to 50% of volunteers; lipopolysaccharide (LPS)-sp ecific IgG1 and IgG3 subclass responses supported the vibriocidal isot ype data, However, following primary exposure, IgG4 LPS responses pred ominated, occurring in 81% of responding volunteers, These data sugges t that, under certain conditions of secondary exposure to V. cholerae O1 antigens, when there is sufficient active local immunity present, t here is a block of vibrio antigen resampling at the M cell level. We d iscuss the implications of and possible explanations for these finding s.