Catching Up on Cholera with the Inventor of the First Effective Oral Vaccine, Dr. Jan Holmgren

Dr. Jan Holmgren won the 2017 Albert B. Sabin Gold Medal for developing the first effective oral cholera vaccine. In light of increasing cholera outbreaks and vaccine shortages, we connected with Dr. Holmgren at the University of Gothenburg in Sweden for his perspective on current cholera vaccine research and development, and what it will take to bring cholera under control.

You recently wrote an opinion article stating that the number of cholera vaccines needed globally has been underestimated.

Absolutely. A realistic estimate would be that we need to have available at least 150-200 million doses of oral cholera vaccine per year. Current production capacity in the world is only 40 million doses. There is almost a five-fold difference in that regard. It poses a serious threat to global goals of eradicating cholera.

What Is the status of the global eradication effort?

On the broad cholera scene, one of the most important efforts happened in the same year I received the Sabin Gold Medal — 2017 — when the World Health Organization (WHO) came together with 50 other international partners and launched a very bold vision for cutting cholera deaths by 90% by 2030. It included maximal use of the available oral cholera vaccines for preventing and counteracting outbreaks, increasing water hygiene and sanitation, as well as developing even more effective vaccines. I have tried to contribute to that by engaging in developing improved vaccines against cholera, mainly through making simplified, easier-to-produce, and thereby, cheaper vaccines.

What improvements are needed to simplify and make the vaccine less expensive?

The two vaccines that are in use today are essentially based upon the vaccine we first developed, the Dukoral vaccine, in Sweden. They have the same composition of bacteria, same formulations, which is relatively complex because we combine both heat-killed and formalin-killed bacteria and there are three different strains. The first simplification, which has just been approved, is from EuBiologics in South Korea and is a simplified version which contains only two of the components of the previous five-component vaccines. (Editor’s Note: Sabin Vaccine Institute is evaluating optimal dosing intervals for this vaccine in Kenya.)

You said the first simplification…are there more?

Yes. We have partnered with the Hilleman Laboratories and also with the Indian company Bharat Biotech, which has a large production capacity, for what I call a second-generation vaccine, which is called HillChol and that is a truly new vaccine which is based on a single engineered strain in a single component, making it correspondingly cheaper. You can produce much larger quantities of it at a lower cost. Hopefully, this vaccine will be licensed and approved by the WHO this year, and that could help overcome current shortages.

But these are liquid vaccines. They are not fully thermostable (stable during storage at higher temperature). So we, with the support of the Wellcome Trust, are collaborating with the International Vaccine Institute to develop what I call a third-generation vaccine. This will be a dry formulation, thermostable, whole cell/B-subunit capsule vaccine that can be stored at 40 degrees hopefully for several years — thereby completely avoiding the need for a cold chain, which would make it a very practical vaccine for cholera.

And the lower cost would make it even more accessible for governments where cholera outbreaks occur…

Cholera is a poverty disease. There is less incentive for the vaccine industry to engage than for many other diseases. It occurs in countries that can least afford vaccines. Anything that makes vaccines less expensive will effectively help reduce the disease. Practically all the money for my research has come from philanthropic sources, such as the government of Sweden, the Wallenberg Foundations, the Bill and Melinda Gates Foundation, and the Wellcome Trust.

Cholera seems to be appearing in more countries today. What is behind all the current outbreaks?

Very clearly, climate change is contributing by leading to more extreme weather with resulting flooding, collapse of existing sanitation systems, collapse of clean water sources and so on. Unfortunately, it appears this will stay with us. Also, an increase in the number of political conflicts and warfare is a second major reason. Yemen has been a tragic example over the last 10 years. And we are seeing, of course, around the world, an increase in the number of conflicts, which breaks down healthcare systems and leads to refugees, which in turn leads to cholera outbreaks. Finally, COVID-19 had a negative impact on vaccination campaigns, which had negative effects on health in many countries and led to increased poverty in the world.

Is cholera growing resistant to antimicrobial treatment like typhoid is?

Earlier, all patients with severe cholera were treated with tetracycline which shortened the disease. Now there is a lot of tetracycline resistance in cholera and also resistance to many of the other commonly used antibiotics as well. Recently, multi-resistant Vibrio cholerae strains have caused outbreaks in several places. So, this is a real problem.

Would adequate vaccine supply help?

I would hope that vaccines will play the role of limiting the spread of antibiotic-resistant cholera strains. But it will need many more doses than are available. Today, we have such a lack of vaccine that all of the supply is needed for fighting current outbreaks. There has been no vaccine available for prevention of cholera in the last year. The lack of vaccine is dramatic and is threatening the whole eradication program. Therefore, vaccines in practice will have a limited effect against antimicrobial resistance right now, which is a rapidly increasing problem.

On the positive side, it doesn’t sound like there is a lot of hesitancy about taking the cholera vaccine.

There have been some attempts in different places to spread deliberate misinformation, but on the whole, the oral cholera vaccine has been highly attractive for most populations. They are lining up to get it when it’s available. Thankfully, oral cholera vaccine does not have the sort of hesitancy problems many other vaccines have.