Safety and Immunogenicity of a Live Oral Recombinant Cholera Vaccine VA1.4: A Randomized, Placebo Controlled Trial in Healthy Adults in a Cholera Endemic Area in Kolkata, India

Abstract

BackgroundA live oral cholera vaccine VA 1.4 developed from a non-toxigenic Vibrio cholerae O1 El Tor strain using ctxB gene insertion was further developed into a clinical product following cGMP and was evaluated in a double-blind randomized placebo controlled parallel group two arm trial with allocation ratio of 1∶1 for safety and immunogenicity in men and women aged 18–60 years from Kolkata, India.MethodA lyophilized dose of 1.9×109 CFU (n = 44) or a placebo (n = 43) reconstituted with a diluent was administered within 5 minutes of drinking 100 ml of a buffer solution made of sodium bicarbonate and ascorbic acid and a second dose on day 14.ResultThe vaccine did not elicit any diarrhea related adverse events. Other adverse events were rare, mild and similar in two groups. One subject in the vaccine group excreted the vaccine strain on the second day after first dose. The proportion of participants who seroconverted (i.e. had 4-folds or higher rise in reciprocal titre) in the vaccine group were 65.9% (95% CI: 50.1%–79.5%) at both 7 days (i.e. after 1st dose) and 21 days (i.e. after 2nd dose). None of the placebo recipients seroconverted. Anti-cholera toxin antibody was detected in very few recipients of the vaccine.ConclusionThis study demonstrates that VA 1.4 at a single dose of 1.9×109 is safe and immunogenic in adults from a cholera endemic region. No additional benefit after two doses was seen.Trial RegistrationClinical Trials Registry-India, National Institute of Medical Statistics (Indian Council of Medical Research) CTRI/2012/04/002582

Immunogenicity and protective efficacy of a live, oral cholera vaccine formulation stored outside-the-cold-chain for 140 days

“…Our RITARD results similar to those of V. cholerae ghost (VCG) vaccine candidate [56] and purified outer membrane vesicle [57] protection against virulent V. cholerae O1 (El Tor) and O139 strains. Similarly, our findings are also in agreement with protection by the live attenuated cholera vaccine VA1.4 against WT O139 in the RITARD model [30].…”

“…An increase in anti-CT IgG/IgA titres would protect the host from cholera by neutralizing CT [61]. The vibriocidal assay has been an indicator to measure the protective efficacy of a vaccine against cholera [30,62]. A four-fold or greater increase in serum vibriocidal antibodies is known to confer protective efficacy of a cholera vaccine [47,52,63].…”

“…Hence, the vaccine candidate must be genetically stable, immunogenic and unable to revert to the pathogenic phenotype. Towards this, several live attenuated vaccines against O1 and O139 are in various stages of development and evaluation with the vaccine candidates CVD-103 HgR [28,29], VA1.3/VA1.4 [30], Peru-15 [31], IEM 101/108/109 [32], Cuban 638 [33,34], Texas Star [35] and Wzm [36], CVD112 [37], Bengal-15 [38], TLP01 [39], VRI-16 [40] and L911/L912 [41]. However, similar to killed cholera vaccines, live vaccine formulations are also heat-sensitive and cold chain supply dependent.…”

Can India lead the way in neglected diseases innovation?

“… 22 23 An oral cholera vaccine that was tested and manufactured in India and has been approved by the World Health Organisation is not yet included as part of the national programme, thereby limiting access. 24 25 Meanwhile, the vaccine was used in Bangladesh during the Rohingya refugee crisis to prevent cholera outbreaks. 26 27…”

Nieuwe vaccins

“…De anti-choleratoxine respons was echter suboptimaal. Verder onderzoek is nodig om te zien of een tweede dosis noodzakelijk is [31].…”