Every year, the Albert B. Sabin Gold Medal Award is given to a distinguished member of the public health community who has made extraordinary contributions in the field of vaccinology. This year's award will honor Jan Holmgren, M.D., Ph.D., for his pioneering contributions to oral vaccine research and mucosal immunology, as well as his leadership in the discovery of the world's first effective oral cholera vaccine. 

Where did your career in scientific research begin? When did you first develop an interest in cholera pathogenesis and immunology?

I started to do research in 1966 in parallel with my medical studies and defended my PhD thesis on the immunology of urinary tract infections in children in 1969. This and additional studies on breast milk antibodies had given me a special interest and training in mucosal immunology. When in 1970 I was about to start my own line of research, I was encouraged by my department chair, Professor Örjan Ouchterlony, to take up cholera as an interesting mucosal immunology research theme. Ouchterlony had then just remet with the famous cholera researcher Robert Phillips – the developer of cholera fluid replacement treatment that is still saving lives today. His argument was that I would then get help from a departmental technician and two interested PhD students – one of which was Ann-Mari Svennerholm, who later became my wife and has been my closest collaborator since 1970.

How did you first begin investigating oral cholera vaccines (OCVs)?

This started in a way more or less directly after we had begun our work on cholera in 1970-71 and in a more focused effort from about 1975. In an early project, one line of research with one of my PhD students, Ivar Lönnroth, focused on the mechanisms of disease in cholera – defining the subunit structure of cholera toxin and identifying its receptor. At the same time, another with Ann-Mari Svennerholm aimed at defining the mechanisms of protective immunity and identifying protective antigens for vaccine development purposes. The latter work – which was supported by the Swedish Bacteriological Laboratory that later became the producer of the Dukoral™ oral cholera vaccine – resulted in Svennerholm´s PhD thesis and led to the paper in Nature in 1977 where we described/proposed the development of a protective cholera vaccine based on inactivated bacterial whole cells and cholera toxin B subunit that should be given by the oral route in order to effectively induce protective IgA intestinal antibodies.

In the 1980s, your group developed the world’s first oral cholera vaccine. How was it different from the injected cholera vaccines that already existed at the time?

Very soon after Robert Koch had described the cholera bacterium, Vibrio cholerae, there came injectable vaccines that were used until the early 1970s. The reason that they were taken out of use and were no longer recommended by the WHO was the fact that in the 1960s, there were several controlled studies demonstrating that these vaccines had a very limited protective effect – maximum of 50 percent protection for usually only 3 months of duration. In addition to that, they were associated with adverse reactions – particularly rather nasty swollen arms – leading to the fact that in cholera-endemic places where there were repeated cholera vaccinations annually or every second year or so, children were actually jumping into the river to get away from these injections because of these painful, swollen arms afterwards. So the combination of adverse reactions and quite limited protective effect led to them being abandoned.

In contrast then, the oral cholera vaccine, even though not being perfect in efficacy give at least 65 percent protection over 3 or 5 year periods. So it’s a marked improvement, plus they are without essentially any adverse reactions. So that’s the reason why also from an effectiveness point of view these oral cholera vaccines are superior. Adding to that – though it was not known at the time when they were first developed – the oral cholera vaccines also give very good herd protection to unvaccinated individuals in the same community. By protecting the vaccinated ones, they reduce the risk of infection also in their neighbors. This combined effect of specific vaccine protection and this indirect herd protection means then that if you can have good coverage – like vaccinating 50 percent or more of the population – you can actually hope to if not eradicate, then extinguish cholera in that setting in a couple years’ time.

Since Dukoral™ was licensed, your group and others have been working hard to develop the next generation of OCVs. How will these vaccines improve on the first OCVs?

Mainly by reduced cost, increased availability, and easier delivery. The already licensed oral cholera vaccines – OrcVax in Vietnam, ShanChol™ in India, and recently Euvichol™ from Korea– are all of them directly based on Dukoral™ (using the same strains and methods). This [reduced cost and easier delivery] is achieved mainly by the local production at lower cost than Dukoral™, and by not requiring any buffer to protect against stomach acidity. The inclusion of B subunit in Dukoral™ adds to the cost and means that the vaccine should be given with a buffer – at the same time the B subunit means that Dukoral™ has better efficacy against cholera than the other whole-cell only vaccines for the first six to nine months after vaccination, and also partly protects against ETEC [enterotoxigenic Escherichia coli] diarrhea.

Therefore, for a few years, we have been actively collaborating with The Hilleman Laboratories in India – and through Hilleman also with Incepta and icddr,b in Bangladesh – to develop and license a truly inexpensive and affordable locally produced oral cholera vaccine. In this vaccine (Hillchol™), the 3-4 bacterial strains and two inactivation methods used in the previously mentioned oral cholera vaccines is replaced by a single-strain/single-formulation whole-cell vaccine based on an engineered “Hikojima serotype” El Tor strain [the dominant strain in many outbreaks over the last century]. Together with improved fermentation methods, this may yield an oral cholera vaccine at a cost of $0.25-0.50 per dose, as compared to $1.85 or more per dose for the currently licensed vaccines. This vaccine is now in clinical testing in Bangladesh, with licensure there aimed for 2018.

A 2nd generation Hillchol-B vaccine under development aims at also including enterocoated [protected from stomach acid, thus requiring no buffer] cholera toxin B subunit, together with the Hikojima whole-cell vaccine in a tablet formulation and/or a practical pediatric double-pouch delivery system, while still maintaining a per dose cost at less than $1.00. This vaccine will also be thermostable, thus avoiding the need for a cold chain for storage and transport of the vaccine.

OCVs are increasingly being used as part of outbreak prevention and response strategies. However, global OCV coverage is still relatively low. What barriers to improving OCV access and uptake remain, and what do you think are the first steps to overcoming them? What do you think should be the global health community’s top priorities regarding OCVs?

The main barrier today I think is the very limited availability of oral cholera vaccines, which I think to a large extent is linked to their poor profitability from the vaccine industry´s economic perspective. Oral cholera vaccines target mainly the poorest populations in the poorest countries and is therefore of no big interest to the pharmaceutical companies for obvious reasons. The main effort is to get oral cholera vaccines for substantially less than $1 per dose, and of course that is not really a priority for the commercial vaccine sector. So I will say this is the toughest barrier both in recent years and in the future for oral cholera vaccines. Unlike rotavirus vaccines, oral cholera vaccines have no real market in the industrialized countries.

Then the second barrier has been the lack of clear and sufficiently strong recommendations by the World Health Organization and others on how to best use cholera vaccines in national controlled programs and in outbreaks. Also, an oral cholera vaccine stockpile has been created, which is a very nice first step, but it’s much too small to have a real impact on cholera from a global perspective.

We would need additional suppliers as well as cheaper costs of production, as increased vaccine use would in itself lead to reduced costs, and I think my recent work together with the Hilleman laboratories – which happens to be a not-for-profit organization but with some money – is a good step in the direction towards cheaper vaccines. And that’s good, but overall I think that in order to get access to the needed volumes of vaccine, I would say 30 million doses for acute cholera control and 100,000 doses for introduction and regular use in endemic countries, there will be a need for committed purchases or donations from bigger not-for-profit sources like the Gates Foundation, the Gavi alliance organization and governments.

There is an outstanding exception to this pattern though: Vietnam has used cholera vaccination since more than 15 years back on a routine basis without getting any much support from the outside apart from some technical help. So there are exceptions, but overall I think that what we’ll need is not-for-profit money going into this together with very clear and strong recommendations to use cholera vaccinations and guidelines also how to use them – in a high-risk country with a limited population like Haiti I would like to see the whole population being vaccinated but currently both there (due to the limitations in vaccine supply) and in larger population cholera endemic countries it would be important to identify which geographic regions and which age groups to target to make best use of the vaccine (in combination with other cholera control measures).

In addition to non-profit money, you said you needed more suppliers. A local company in Bangladesh has reportedly begun making a domestic version of Sanchol. What role, if any, do you think local vaccine manufacturing will play in expanding oral cholera vaccine coverage?

Developing countries didn’t use to have the technology to make reliable vaccines, but this has now dramatically changed for the majority of vaccines. Now a large number of excellent local manufacturers are actually producing the majority of currently used vaccines for the Expanded Programme on Immunization. So this has changed dramatically over time and there are excellent manufacturers in many places in developing countries. Therefore, I think that barrier has completely disappeared and there would be many developing countries that could manufacture excellent oral cholera vaccine at affordable cost. I think it would be relatively easy to stimulate local vaccine production in several places, but there would be a need first for clear recommendations both internationally and by national governments, and of course some technical and financial support to help production to come in place.

What developments on the horizon for OCV research are you particularly excited about, and why are they so promising for the future of cholera prevention?

Much cheaper and thermo-stable oral cholera vaccines, ideally also containing B subunit in practical formulations and delivery systems for public health use. One limitation with the Dukoral™ vaccine that we developed is the need for co-administration with a bicarbonate-based buffer in order to protect the [cholera toxin] B subunit component of the vaccine from stomach acidity. So that was something that I learned over time, that bicarbonate actually complicates delivery a bit – not so that it is a strong barrier but it is a limitation for mass vaccination purposes. This may be overcome by enterocoating either the B subunit component and mixing it with liquid vaccine at the time of administration, or by creating a tablet formulation that is enterocoated to protect both the bacterial component and the B subunit. So the tablet formulation could have some advantages, also because it is easy to package, easy to transport, easy to store and by being a dry formulation, it would also be thermostable over a long time.

So the tablet formulation is from several points of view an important technical advancement, with one exception. And that is that tablets are not allowed in developing countries for children below the age of five years – or at least not below the age of three years – because if you are unlucky, the tablet could go in the wrong place and get in the airways and cause big problems. This is the reason why we started to work with Hilleman Laboratories – I knew that Hilleman [Laboratories] was working on trying to develop practical formulations for delivery of rotavirus vaccines. Work is underway to develop a pediatric double-pouch formulation, wherein you have the enterocoated B subunit in one compartment and in the other you have the liquid vaccine, and you press the liquid vaccine with your thumb into the enterocoated B subunit and push the mixture into the mouth of the small child. So it might be that a tablet for adults and older children and a pediatric formulation with the double pouch may both be developed and would be advantageous.

 

This interview was edited for clarity and length.