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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 industryFor 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)
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A Deferred-Vaccination Design to Assess Durability of COVID-19 Vaccine Effect After the Placebo Group Is VaccinatedMultiple candidate vaccines to prevent COVID-19 have entered large-scale phase 3 placebo-controlled randomized clinical trials, and several have demonstrated substantial short-term efficacy. At some point after demonstration of substantial efficacy, placebo recipients should be offered the efficacious vaccine from their trial, which will occur before longer-term efficacy and safety are known. The absence of a placebo group could compromise assessment of longer-term vaccine effects. However, by continuing follow-up after vaccination of the placebo group, this study shows that placebo-controlled vaccine efficacy can be mathematically derived by assuming that the benefit of vaccination over time has the same profile for the original vaccine recipients and the original placebo recipients after their vaccination. Although this derivation provides less precise estimates than would be obtained by a standard trial where the placebo group remains unvaccinated, this proposed approach allows estimation of longer-term effect, including durability of vaccine efficacy and whether the vaccine eventually becomes harmful for some. Deferred vaccination, if done open-label, may lead to riskier behavior in the unblinded original vaccine group, confounding estimates of long-term vaccine efficacy. Hence, deferred vaccination via blinded crossover, where the vaccine group receives placebo and vice versa, would be the preferred way to assess vaccine durability and potential delayed harm. Deferred vaccination allows placebo recipients timely access to the vaccine when it would no longer be proper to maintain them on placebo, yet still allows important insights about immunologic and clinical effectiveness over time.
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Persisting antibody responses to Vi polysaccharide-tetanus toxoid conjugate (Typbar TCV®) vaccine up to 7 years following primary vaccination of children < 2 years of age with, or without, a booster vaccinationBackground: Serum IgG anti-Vi titers attained by 327 children 6–23 months of age immunized with Vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar TCV®), of whom 193/327 received a booster dose 2 years post-primary vaccination, were previously reported. Methods: Anti-Vi IgG in boosted and unboosted children 3, 5, and 7 years post-primary immunization were monitored using three different enzyme-linked immunosorbent assays (ELISAs): Vacczyme™ kit ELISA (all specimens); “Szu” ELISA (all specimens), and National Institute of Biological Standards NIBSC ELISA (subset). Endpoints analyzed included: persisting seroconversion (titer remaining ≥ 4-fold above baseline), geometric mean titer (GMT), geometric mean-fold rise post-vaccination, and percent exhibiting putative protective anti-Vi level (≥2 µgSzu/ml) using Szu method and National Institutes of Health IgG reference standard. In assessing the persistence of elevated anti-Vi titers stimulated by Typbar-TCV®, four subgroups were compared based on whether or not the initially enrolled children were boosted on day 720 and whether they provided serum on all key timepoints, or if they missed one or more timepoints: i) Among boosted participants, an “All Specimens Cohort” (ASC) comprised 86 children who provided sera on days 42, 720 (booster), 762 (42 days post-booster), 1095, 1825 and 2555, to define kinetics of the Vi antibody response in a fully compliant cohort of boosted children monitored over seven years; ii) Among non-boosted subjects, a compliant All Specimens Cohort of 25 children provided sera on days 0, 42, 720, 1095, 1825, and 2555; iii) Among boosted children, an “Any Available Specimen” (AAS) subgroup consisted of boosted children who provided sera on days 0, 42, and 720 days and also on one or more of days 762, 1095, 1825, or 2555 but not on all those time points; iv) Among the non-boosted subjects, there was also an Any Available Specimen subgroup of 47 children who provided sera on days 0 and 42, of whom 41 subsequently contributed sera on one or more of days 1095, 1825 and 2555. Results: Vacczyme™ GMTs among boosted ASC children (N = 86) increased significantly on day 762, and remained 32-fold, 14-fold, and 10-fold over baseline at 3, 5 and 7 years; among unboosted ASC children (N = 25), GMTs remained 21-fold, 8-fold and 5-fold over baseline, respectively. Post-primary vaccination, 72% and 44% of unboosted ASC subjects (N = 25) exhibited persisting seroconversion by Vacczyme™ at 5 and 7 years, respectively; the corresponding numbers for ASC boosted subjects were 84% and 71%. Amongst the four sub-groups, boosted subjects showed higher prevalence of persisting seroconversion at most time points with the gap widening by 7th year, though not statistically significant (except 3rd year). Tested by Szu and also NIBSC ELISAs, 92–100% of unboosted ASC children showed persisting seroconversion at 7 years with 100% also exceeding the Szu protective threshold. Conclusion: To extend protection, administering a booster of Typbar TCV® to children ∼5 years after their primary dose, i.e., coinciding with school entry, may be advisable. Typbar TCV® is presently the only WHO pre-qualified Vi conjugate vaccine with reported efficacy, effectiveness, and long-term immunogenicity findings.
