Editorial Commentary: Resurrecting a Live Oral Cholera Vaccine

(See the Major Article by Chen et al on pages 1329–35.)

Access to clean water and sanitation is the best defense against cholera, but >650 million people live without clean water, and >2 billion people lack access to improved sanitation [1]. When a pandemic strain of Vibrio cholerae was introduced in Haiti in October 2010, >80% of the population lacked safe water and basic sanitation, and cholera spread rapidly. Five years later, V. cholerae remains entrenched in Haiti and has resulted in >750 000 reported cases of cholera and >9000 reported deaths [2].

The epidemic in Haiti spurred the World Health Organization to develop a cholera vaccine stockpile. With support from Gavi, the Vaccine Alliance, this stockpile is being increasingly utilized to vaccinate vulnerable populations and control cholera epidemics around the world. There is also now hope that the use of vaccines could be expanded to control, or perhaps even eliminate, cholera in endemic areas.

The increasing use of cholera vaccines over the last few years represents significant progress in an otherwise very bumpy road. Although the first inactivated, whole-cell injectable cholera vaccines were developed more than a century ago, they were abandoned in the 1970s because they were too reactogenic and provided only short-lived protection. The second generation of cholera vaccines, developed in the 1980s, were administered orally and initially included both inactivated whole-cell and live attenuated vaccines. At present, however, only inactivated whole-cell cholera vaccines are commercially available and World Health Organization prequalified. Among these is Dukoral (Crucell, Netherlands), the first licensed oral cholera vaccine, derived from inactivated V. cholerae O1 and recombinant cholera toxin B subunit. Dukoral is primarily used as a vaccine for travelers to cholera-endemic areas. Two newer bivalent inactivated vaccines, however, are being produced with the intention that they be used in cholera-endemic areas: Shanchol (Shantha Biotechnics, India) and Euvichol (EuBiologics, Korea). These bivalent vaccines include inactivated V. cholerae serogroups O1 and O139, although the latter has not been a significant cause of cholera in more than a decade. These vaccines do not include recombinant cholera toxin B subunit. Compared to Dukoral, the newer bivalent vaccines confer longer-lasting protection and are significantly less expensive.

What happened to the live attenuated cholera vaccines? In this issue of Clinical Infectious Diseases, Chen and colleagues effectively resurrect the attenuated oral cholera vaccine, CVD 103-HgR [3]. CVD 103-HgR was developed in the 1980s and was commercially available outside the United States from 1994 to 2004. After acquiring the license for CVD 103-HgR, PaxVax (Redwood City, California) reformulated the vaccine. Working with PaxVax and colleagues at 3 academic centers in the United States, Chen et al performed a multisite human challenge study to evaluate the efficacy of the reformulated vaccine. This provides a timely opportunity to revisit whether there is a role for live attenuated vaccines in the current dynamic landscape of cholera vaccines.

In their study, Chen et al found that the protective efficacy of a single dose of CVD 103-HgR against moderate to severe diarrhea due to V. cholerae O1 El Tor Inaba was 90% at 10 days after vaccination, and 80% at 3 months after vaccination. Even though ciprofloxacin was given to participants who experienced >5 liters of diarrhea (aborting the full effect of cholera), the challenged placebo recipients still had a median output of approximately 22 stools, corresponding to 4.4 liters of diarrhea. In contrast, the median output of vaccinees challenged at 3 months was 2 stools and <200 mL of diarrhea. Vaccination also decreased the shedding of viable bacteria upon challenge, a critical point to the potential for indirect protection. Also importantly, Chen and colleagues found that vibriocidal antibody seroconversion was strongly predictive of protection, demonstrating that the vibriocidal antibody is an appropriate proxy of vaccine efficacy, at least for short-term protection. No adverse events or side effects from the vaccine were observed in the cohort, and these results are similar to those seen in earlier challenge studies of CVD 103-HgR [4].

Based on these results, there is strong evidence that a single dose of the reformulated CVD 103-HgR vaccine will provide protection against cholera in adults from developed countries who are traveling to cholera-endemic areas and are at increased risk for infection. This would be especially relevant for humanitarian relief workers and first responders, in settings such as complex emergencies or refugee camps that are threatened by epidemic cholera. In this setting, a single-dose vaccine would have an advantage over the current inactivated whole-cell vaccines, which currently require 2 doses given over 14 days. The addition of a safe and effective US Food and Drug Administration–approved cholera vaccine would also be especially welcome in the United States, where no cholera vaccines are currently available.

But what about the much larger number of people who are impacted by cholera because they live in endemic areas or are vulnerable to epidemics of cholera—could this vaccine help them?

The answer is that although CVD 103-HgR holds promise, there are obstacles to overcome. First, CVD 103-HgR has a complicated track record in areas where cholera is endemic. Past experience suggests that a higher-dose formulation is needed to achieve sufficient immune responses in populations where endemic cholera occurs. In addition, the one placebo-controlled trial of CVD 103-HgR that has been performed in a cholera-endemic area to date demonstrated a protective efficacy of only 14% [5]. This study was likely fatally flawed as it did not account for indirect protection (otherwise known as herd immunity), which is now recognized as a critical element in assessing cholera vaccines [6]. Furthermore, the results of this clinical trial stand in contrast to the success of the vaccine in a reactive vaccination campaign in 2000 in Micronesia, where the actual protective effectiveness of the vaccine was estimated at 80% over a 10-month follow-up period [7].

So is the reformulated version of CVD 103-HgR worth reevaluating for people living in cholera-endemic areas or who are at risk for epidemic cholera? The answer to this will depend on the cost of the vaccine and the feasibility of delivering it under field conditions. In particular, the cold chain requirements for the live attenuated vaccine could increase the cost and difficulty of vaccine delivery, although cold chain storage is also currently required for inactivated oral cholera vaccines. And although a single-dose vaccine has obvious advantages in the setting of a reactive vaccination campaign, the ability to rapidly produce or stockpile a large supply of the vaccine may also determine whether the vaccine could be used in a humanitarian crisis. While these obstacles may not be insurmountable, it will clearly take a significant commitment to advance CVD 103-HgR to the point where it could be used to help those at greatest risk of dying from cholera.

Note

Potential conflict of interest. J. B. H. has served on the data safety and monitoring board for the PXVX-VC-200-003 challenge study and on a scientific advisory committee for PaxVax. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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