A randomized, placebo-controlled, double-blind Phase 2 trial comparing the reactogenicity and immunogenicity of a single ≥2x108 colony forming units [cfu] standard-dose versus a ≥2x109 cfu high-dose of CVD 103-HgR live attenuated oral cholera vaccine, with Shanchol inactivated oral vaccine as an open label immunologic comparator
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Other TitlesHigh-dose vs standard-dose live oral cholera vaccine
AbstractReactive immunization with a single-dose cholera vaccine that could rapidly (within days) protect immunologically-naïve individuals during “virgin soil” epidemics would facilitate cholera control. One dose of attenuated Vibrio cholerae O1 classical Inaba vaccine CVD 103-HgR (VaxchoraTM) containing >2x108 colony forming units (cfu) induces vibriocidal antibody seroconversion (correlate of protection) in >90% of U.S. adults. A previous CVD 103-HgR commercial formulation required >2x109 cfu to elicit high seroconversion in developing country populations. We compared vibriocidal responses of Malians (18-45 years old) randomized to ingest a single >2x108 cfu standard-dose (N=50) or >2x109 cfu high-dose (N=50) of PaxVax CVD 103-HgR with buffer, or two doses (N=50) of ShancholTM inactivated cholera vaccine (the immunologic comparator). To maintain blinding, participants were dosed twice, 2 weeks apart; CVD 103-HgR recipients ingested placebo weeks before or after ingesting vaccine. Seroconversion (>4-fold vibriocidal titer rise) between baseline and 14 days after CVD 103-HgR, and following the first and second dose of Shanchol were the main outcomes measured. By day 14 post-vaccination, seroconversion after a single standard-dose of CVD 103-HgR was 71.7% (33/46) and 83.3% (40/48) after high-dose. Seroconversion following first-dose Shanchol 56.0% (28/50) was significantly lower compared with high-dose CVD 103-HgR (p=0.003). High-dose CVD 103-HgR vibriocidal geometric mean titer (GMT) exceeded standard-dose GMT at day 14 (214 vs 95, p=0.045) and was ~2-fold higher than day 7 and day 14 GMT following the first Shanchol dose (p>0.05). High-dose CVD 103-HgR is recommended for accelerated evaluation in developing countries to assess efficacy and practicality in field situations. (ClinicalTrials.gov number, NCT02145377)
DescriptionAdditional authors: Haidara, Fadima C.; Kotloff, Karen L.; Pasetti, Marcela F.; Blackwelder, William C.; Traore, Awa; Tamboura, Boubou; Doumbia, Moussa; Diallo, Fatoumata; Coulibaly, Flanon; Onwuchekwa, Uma; Kodio, Mamoudou; Tennant, Sharon M.; Reymann, Mardi; Lam, Diana F.; Gurwith, Marc; Lock, Michael; Yonker, Thomas; Smith, Jonathan; Simon, Jakub K.; and Levine, Michael M.
live oral vaccine
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/7401
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Early smallpox vaccine manufacturing in the United States: Introduction of the "animal vaccine" in 1870, establishment of "vaccine farms", and the beginnings of the vaccine industryEsparza, J.; Lederman, S.; Nitsche, A. (Elsevier Ltd, 2020)For the first 80-90 years after Jenner's discovery of vaccination in 1796, the main strategy used to disseminate and maintain the smallpox vaccine was arm-to-arm vaccination, also known as Jennerian or humanized vaccination. A major advance occurred after 1860 with the development of what was known as "animal vaccine", which referred to growing vaccine material from serial propagation in calves before use in humans. The use of "animal vaccine" had several advantages over arm-to-arm vaccination: it would not transmit syphilis or other human diseases, it ensured a supply of vaccine even in the absence of the spontaneous occurrence of cases of cowpox or horsepox, and it allowed the production of large amounts of vaccine. The "animal vaccine" concept was introduced in the United States in 1870 by Henry Austin Martin. Very rapidly a number of "vaccine farms" were established in the U.S. and produced large quantities of "animal vaccine". These "vaccine farms" were mostly established by medical doctors who saw an opportunity to respond to an increasing demand of smallpox vaccine from individuals and from health authorities, and to make a profit. The "vaccine farms" evolved from producing only smallpox "animal vaccine" to manufacturing several other biologics, including diphtheria- and other antitoxins. Two major incidents of tetanus contamination happened in 1901, which led to the promulgation of the Biologics Control Act of 1902. The US Secretary of the Treasury issued licenses to produce and sell biologicals, mainly vaccines and antitoxins. Through several mergers and acquisitions, the initial biologics licensees eventually evolved into some of the current major American industrial vaccine companies. An important aspect that was never clarified was the source of the vaccine stocks used to manufacture the smallpox "animal vaccines". Most likely, different smallpox vaccine stocks were repeatedly introduced from Europe, resulting in polyclonal vaccines that are now recognized as "variants" more appropriately than "strains". Further, clonal analysis of modern "animal vaccines" indicate that they are probably derived from complex recombinational events between different strains of vaccinia and horsepox. Modern sequencing technologies are now been used by us to study old smallpox vaccine specimens in an effort to better understand the origin and evolution of the vaccines that were used to eradicate the smallpox. Copyright 2020 The Author(s)
Anti-O-specific polysaccharide (OSP) immune responses following vaccination with oral cholera vaccine CVD 103-HgR correlate with protection against cholera after infection with wild-type Vibrio cholerae O1 El Tor Inaba in North American volunteersIslam, K.; Hossain, M.; Kelly, M. (Public Library of Science, 2018)Background: Cholera is an acute voluminous dehydrating diarrheal disease caused by toxigenic strains of Vibrio cholerae O1 and occasionally O139. A growing body of evidence indicates that immune responses targeting the O-specific polysaccharide (OSP) of V. cholerae are involved in mediating protection against cholera. We therefore assessed whether antibody responses against OSP occur after vaccination with live attenuated oral cholera vaccine CVD 103-HgR, and whether such responses correlate with protection against cholera. Methodology: We assessed adult North American volunteers (n = 46) who were vaccinated with 5 × 108 colony-forming units (CFU) of oral cholera vaccine CVD 103-HgR and then orally challenged with approximately 1 × 105 CFU of wild-type V. cholerae O1 El Tor Inaba strain N16961, either 10 or 90 days post-vaccination. Principal findings: Vaccination was associated with induction of significant serum IgM and IgA anti-OSP and vibriocidal antibody responses within 10 days of vaccination. There was significant correlation between anti-OSP and vibriocidal antibody responses. IgM and IgA anti-OSP responses on day 10 following vaccination were associated with lower post-challenge stool volume (r = −0.44, P = 0.002; r = −0.36, P = 0.01; respectively), and none of 27 vaccinees who developed a ≥1.5 fold increase in any antibody isotype targeting OSP on day 10 following vaccination compared to baseline developed moderate or severe cholera following experimental challenge, while 5 of 19 who did not develop such anti-OSP responses did (P = 0.01). Conclusion: Oral vaccination with live attenuated cholera vaccine CVD 103-HgR induces antibodies that target V. cholerae OSP, and these anti-OSP responses correlate with protection against diarrhea following experimental challenge with V. cholerae O1. Copyright 2018 Public Library of Science. All Rights Reserved.