Regulatory Hurdles
In addition to regulations governing all vaccines, LBVs face additional regulatory hurdles. First, they must achieve the right
balance between safety and immunogenicity. Additional issues include the potential for genetic reversion to partial or full
pathogenicity, gene transfer into and out of the vaccine cells, and the potential risks for humans and the environment. For
many vaccine candidates, the appropriate balance of attenuation and immunogenicity could not be met, and development of such
candidates was consequently discontinued at an early stage of clinical evaluation. For the trivalent oral polio vaccine, which
has been licensed for decades, it is known that reversion to virulence occurs quite often in the gastrointestinal tract of
vaccinated individuals. This reversion to wildtype is a common cause of disease when a virus is shed and transmitted to nonimmune
household contacts. Hence, these safety issues have to be addressed very carefully during preclinical and clinical development.
Determining Safety and Efficacy
In the case of Ty21a, safety and efficacy of the vaccine were demonstrated in a large number of clinical trials, with over
500,000 vaccinated children and adults in the US, Europe, Africa, Latin America, and Asia. Excellent tolerability and an overall
protective efficacy of 67–80% were demonstrated for up to seven years in large field trials.5 The safety and tolerability profile of Ty21a was further confirmed in more than 200 million vaccinees during its more than
25-years of use worldwide. Recent postmarketing surveillance has identified only mild and infrequent adverse events associated
with Ty21a. From 1990 to 2000, more than 38 million people were vaccinated with Ty21a with only 743 spontaneous reports of
adverse events, an incidence of 0.002%. The most common adverse events reported with Ty21a were mild and transient gastrointestinal
disturbances, followed by general symptoms such as pyrexia.
As mentioned above, the most important safety feature is to demonstrate that the vaccine strain is unable to revert to a virulent
phenotype during production, inside the human body and after potential excretion of the vaccine strain, if applicable. For
Ty21a, reversion to virulence has not been observed in vitro or in vivo during the more than 30 years since the strain was developed. No mutations were found in master and working seed lots produced
over a 25-year period in genetic stability studies, nor was any reversion found in clinical trials. Clinical trials have also
shown either a limited and transient level or a complete lack of shedding in the stools of volunteers depending on the administered
dose of Ty21a. With a 10-fold overdose, mainly on day one post-vaccination, a low rate of excretion was observed. Further
studies showed a lack of fecal excretion of Ty21a upon administration of the commercial formulation. The reason for the low
excretion rate is probably the limited ability of the vaccine strain to proliferate in vivo. However, if there is excretion, additional studies need to be performed. In the case of Ty21a, these included an analysis
of vaccine strain transmission to household contacts, which was not observed for Ty21a. Furthermore, Ty21a demonstrated a
limited ability to survive in the environment because of its auxotrophy and reduced stress resistance, therefore not posing
environmental risks.
The clinical program was somewhat different for CVD 103-HgR. For V. cholerae, a human challenge model exists. This means that after vaccination, humans can be infected intentionally with wildtype, fully
virulent V. cholerae bacteria to determine whether the vaccine is indeed efficacious against infection and disease. In the volunteer challenge
model, significant efficacy of CVD 103-HgR against wildtype V. cholerae challenge infection was demonstrated in North American adults as early as eight to 10 days after vaccination and for at least
six months.10 Hence, oral vaccination with CVD 103-HgR is highly suitable to elicit protective immunity in North Americans, as shown in
trials that are comparatively easy to perform. However, challenge trial results in North American adults may have limited
relevance for the vaccines' protective efficacy in cholera-endemic areas of the world. Hence, a field trial was performed
in Indonesia with CVD 103-HgR. Unfortunately, protective efficacy of CVD 103 HgR could not be demonstrated in this field trial.
More than 60,000 children and adults were given either vaccine or placebo. However, cholera was virtually absent in Indonesia
after initiating the clinical trial, and therefore, there were almost no cholera cases in the vaccine and the placebo group.
This made it almost impossible to calculate a protective efficacy for the vaccine in this particular setting. This exemplifies
the challenges vaccine field trials can pose.
In many controlled studies and after a decade of postmarketing experience, CVD 103-HgR has been shown to be safe and well
tolerated. In diverse populations, no adverse reactions occurred significantly more often in vaccinees than in placebo recipients.10
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