Thermotolerant vaccines: A game changer?

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The Serengeti Health Initiative (SHI)—co-funded by Washington State University and Lincoln Park Zoo (Chicago)—has, since 2003, been controlling rabies through the implementation of annual mass dog rabies vaccination campaigns in remote villages in northern Tanzania. The effectiveness of campaigns such as these, and the epidemiological features that make elimination feasible (e.g., effective vaccines are available; domestic dogs, not wildlife, are the reservoir of infection; and rabies has a relatively low R0 (the number of secondary infections produced from a primary case)) have led the World Health Organization (WHO), together with the Food & Agricultural Organization (FAO) and the World Organization for Animal Health (OIE), to recognize canine-mediated human rabies as a global health priority and to unite in a tripartite commitment to its global elimination by 2030. Whether this commitment is met with success will, in part, be determined by vaccine delivery programs being able to overcome the logistical problems associated with ramping up from the small to the regional scale.

One constraint that poses a particular problem is the difficulty of achieving vaccination coverage of 70% of the dog population consistently across the vast and remote rural landscapes that characterize much of sub-Saharan Africa and Asia. With the elimination of rabies critically dependent on contiguous vaccination coverage, even small pockets of low coverage (e.g., involving < 0.5% of the dog population) will cause significant delay. Consequently, if the large, coalescent, disease-free zones necessary for regional elimination are to be created, it will be essential to overcome this constraint. 

One factor hampering the delivery of sufficient quantities of rabies vaccines to hard-to-reach areas is the lack of electrical power needed to maintain the cold-chain. As a result the transport and storage of vaccines in remote locations is compromised. Consequently entire communities are, at best, dependent on donor-funded team-led vaccination campaigns or, at worst, receive no rabies control at all. Moreover, in those communities that are fortunate enough to be targeted, the inability to store vaccines in these locations means that any new dogs that enter the population such as puppies must remain unvaccinated until the next campaign event passes through. When this immigration of unvaccinated dogs is coupled with a high mortality rate (life expectancy of dogs in rabies endemic countries < 3 years), the result is the proportion of immunized dogs decreasing steadily following each campaign. If coverage falls below a critical threshold then R0 will become greater than 1, and, if virus enters the population, rabies will be sustained.

A potential solution to this problem of how vaccines can be delivered to and stored in remote areas is thermotolerance–the ability of a vaccine to retain its potency following storage at temperatures in excess of the cold-chain (4 °C).  Indeed, thermotolerance has been cited as a critical aspect of the successful campaigns to eliminate both rinderpest and small pox because it empowered local communities to coordinate and deliver their own campaigns using vaccines safely stored for extended periods outside of the cold-chain, greatly increasing the reach of both campaigns. If rabies vaccines can also be shown to be thermotolerant, this could have an equally transformative effect on the global elimination of canine-mediated rabies.

A boxplot showing the range of (2log) day-28 titres produced by vaccine stored at elevated temperatures for zero (cold-chain), three or six months (red diamond = 2log titre mean; G1 – 7 = treatment groups 1 – 7).To this end, in 2015–16, a collaborative project between WSU and MSD Animal Health began investigating whether the commonly-used canine rabies vaccine Nobivac® Rabies had thermotolerant properties. The first phase of this trial, which investigated the effect that various levels of non cold-chain storage had on the potency of the vaccine, indicated that this vaccine retained its efficacy following storage at 25°C for six months and 30°C for three months. These results are extremely exciting as they provide the first evidence that this vaccine can be safely used following extended storage in conditions well outside of the cold-chain. Further, the results suggest that more cost-effective delivery strategies, potentially involving communities managing and implementing their own campaigns, can be developed.  If successful these developments could transform how mass dog rabies vaccination is delivered to hard-to-reach communities where rabies remains stubbornly endemic. Given the tripartite agreement for global elimination of rabies, these developments will be particularly timely. 

Submitted by Felix Lankester, Clinical Assistant Professor, Paul G. Allen School for Global Animal Health, Washington State University. The study "Thermotolerance of an inactivated rabies vaccine for dogs" has just been published in Vaccine.