Gonorrhoea is an old affliction. The book of Leviticus mentions a contagious condition involving the continuous emission of semen and a painful erection. Only 2,500 years later, in the mid-20th century, did the discovery of antibiotics bring relief.
But not, perhaps, for long. Decades of exposure to antibiotics have led N. gonorrhoeae, the bacterium that causes the disease, to develop resistance. With few new antibiotics coming onto the market, the bug is once again gaining the upper hand. Failures of treatment are being reported in many countries. It is now designated a “priority” pathogen by the World Health Organization. https://www.economist.com/science-and-technology/2023/11/01/a-new-gonorrhoea-drug-was-developed-by-a-non-profit-foundation?
The news on 01 November that zoliflodacin, a new antibiotic, had been successful in a clinical trial was thus welcome. The drug inhibits an enzyme called type II topoisomerase, which, among other things, is vital to bacterial reproduction. More interesting than how zoliflodacin works, though, is how it came into being. Most drugs are developed by private companies. Zoliflodacin was created with the assistance of the American government and the Global Antibiotic Research and Development Partnership (GARDP), a non-profit outfit funded by a mix of organisations including the Wellcome Trust, a big charity, and the Swiss canton of Geneva.
GARDP worked with Innoviva Speciality Therapeutics, an American pharmaceutical firm. The company handled early development, and is shepherding the drug through registration with the Food and Drug Administration. The National Institute of Allergy and Infectious Diseases guided it through its phase 2 trials, which check whether a new drug works. GARDP supported the drug through subsequent, much bigger phase 3 trials, the final stage before a drug is approved for use. Its support allowed those trials to be tailored to public health goals—such as including in the trials higher-risk patients such as women, adolescents and people with HIV.GARDP is also handling the licensing, which it hopes will make zoliflodacin cheap and widely available.
Duncan Graham-Rowe, a spokesman for GARDP says such partnerships could boost the supply of new antibiotics. (Another non-profit, carb-x, is doing similar work.) The dearth of new drugs in recent decades mainly reflects poor incentives. To delay the development of resistance, new antibiotics need to be kept in reserve until they are really needed. But a drug that spends years on the shelf is not commercially attractive.
Governments have tried to fix that problem with ideas such as guaranteed prices and annual payments that are made even if the drugs are not used. State-run drug firms have been mooted too. It will take more than zoliflodacin to show that GARDP has found a winning formula. But the signs are good: it is developing four other antibiotics, including one for complicated urinary tract infections, and more are on the way.
Several children born deaf can now hear after receiving gene therapy. The children, from China, had inherited two defective copies of the gene encoding otoferlin, a protein that helps the inner ear transmit sound to the brain. A team at Fudan University injected harmless viruses carrying DNA for a working copy of the hearing gene into one inner ear of each child. Four of five kids treated now have some hearing, the team reported last week at the annual meeting of the European Society for Gene and Cell Therapy in Belgium, according to the group’s conference abstract and MIT Technology Review.
The U.S. company Regeneron last week reported similar success for the first child treated with its comparable gene therapy. Deafness due to mutations in otorferlin’s gene is rare— it explains up to 8% of cases of inherited deafness—but the results offer hope for treating other genetic forms of deafness. https://www.science.org/content/article/news-glance-avian-flu-gene-therapy-setback-and-opera-about-fraudulent-researcher
The first vaccine against the mosquito-borne viral disease chikungunya will likely come to market next month. With the debilitating disease now afflicting more than half the countries in the world and threatening to spread further, the imminent U.S. Food and Drug Administration (FDA) approval of the vaccine is “great news,” says Scott Weaver, a virologist at the University of Texas Medical Branch whose own lab started to work on a chikungunya vaccine nearly 2 decades ago. https://www.science.org/content/article/chikungunya-vaccine-nearing-approval-who-will-get-it?
The vaccine, made by the French company Valneva, will likely be recommended mainly to U.S. travellers at first. But many expect an FDA approval will also grease the wheels for the vaccine to become available in the most affected countries.
First documented in 1952 in modern-day Tanzania, chikungunya means “disease that bends up the joints” in Kimakonde, an East African language. Although rarely fatal, chikungunya virus causes long-term, debilitating joint pain in up to 40% of people it infects, most of whom live in warm climates that have large populations of two mosquito species, Aedes aegypti and A. albopictus. Almost all cases in the United States have been in travellers who have returned from affected countries.
The vaccine consists of a lab-weakened version of the virus that does not cause disease, and it is likely to be approved without the usual efficacy data from human trials. FDA agreed with Valneva—and wide consensus in the field—that a standard efficacy trial comparing rates of disease in people who receive the vaccine versus dummy shots was not feasible. “The virus spreads tremendously fast,” leaving too little time to launch and complete a trial, says Barbara Schnierle, a virologist at the Paul Ehrlich Institute who studies chikungunya.
Valneva instead staged studies that showed 99% of people who received a single shot developed long-lasting antibodies that could neutralize the virus in test tubes. The company went on to show that when it infused monkeys with these antibodies and then gave them the virus, the animals controlled viral levels and did not develop any symptomatic disease. If the vaccine wins approval, FDA will require Valneva to conduct a post market study in humans to evaluate whether it actually protects against disease in the real world.
Valneva’s expected approval comes after years of frustratingly slow progress. More than 5 decades ago, the U.S. Army made a chikungunya vaccine that protected monkeys and even entered a small human trial, but the military saw little need for it and didn’t advance the research. Other efforts similarly languished, in part because at the time, the disease surfaced only sporadically in a few African and Asian countries.
In 2004, Kenya had the world’s first documented large-scale outbreak of chikungunya in 30 years. The next year, a large outbreak hit Réunion Island, an overseas territory of France in the Indian Ocean that had never detected a case. Estimates suggest nearly 40% of the population was infected, and 85% of people developed debilitating symptoms.
Analyses of the circulating virus showed it had mutated to allow replication in the A. albopictus mosquitoes, which have a different range from its original host, A. aegypti. The virus also became better at copying itself in both species, increasing transmission to humans. Outbreaks soon exploded in India, Thailand, the Caribbean, and Brazil. Chikungunya did so well that in many locales, it bumped out dengue virus, which the same mosquito species transmit. To date, more than 100 countries have reported local transmission of the virus.
Serious interest in vaccines finally ramped up—including the one made by Valneva, which it licensed from a group at the Karolinska Institute. An inactivated virus candidate from India’s Bharat Biotech, which may be safer for pregnant and immunocompromised people, is close on the heels of the Valneva shot.
Among the countries that could really use the vaccine are Brazil and Paraguay, which together have seen 75% of the world’s 440,000 reported chikungunya cases this year. Brazil’s Butantan Institute is now partnering with Valneva to bottle the vaccine and make it affordable there and to other middle- and low-income countries.
Climate change may make chikungunya vaccines even more important. Warming climates are altering mosquito populations, which Schnierle notes are already moving north in Europe. “We’ve had local outbreaks in Italy, Spain, and France from travellers coming back from tropical countries,” Schnierle says. “Climate change will change the whole situation.”
Three cities in Colombia saw a dramatic fall in the incidence of dengue in the years following the introduction of mosquitoes carrying Wolbachia, a bacterium that prevents the insect from transmitting viruses. In neighbourhoods where the Wolbachia mosquitoes were well established, dengue incidence dropped by 94–97%.
The Aedes aegypti mosquitoes were released by the World Mosquito Program (WMP), a non-profit organization that has been conducting similar experiments in Australia, Brazil, Indonesia and Vietnam, among other countries. In Colombia, the modified mosquitoes were released in one of the country’s most populous regions. “That’s the largest continuous releases of Wolbachia [mosquitoes] globally so far, in terms of the population covered and the area,” says Katie Anders, an epidemiologist at the WMP and Monash University in Melbourne, Australia.
Anders presented the results on 22 October at the annual meeting of the American Society of Tropical Medicine and Hygiene in Chicago, Illinois.
When infected with Wolbachia, the mosquitoes are much less likely to transmit diseases such as dengue and Zika, because the bacteria compete with these viruses. The insects also pass the bacteria on to their offspring. Researchers hope that the modified mosquitoes will interbreed with the wild population wherever they are released, and that the number of mosquitoes with Wolbachia will eventually surpass that of mosquitoes without it.
The gold standard for evaluating the efficacy of a public-health intervention is randomized controlled trials. The WMP has conducted one such study in Yogyakarta, Indonesia, in which mosquitoes were released in some areas of a city and the incidence of dengue was compared with that in areas that did not receive the insects. The results suggested that the technology could reduce the incidence of dengue by 77%1. The organization is now conducting a similar one in Belo Horizonte, Brazil.
Despite the positive results, Wolbachia mosquitoes have not yet been officially endorsed by the World Health Organization (WHO). The technology awaits an evaluation by the WHO’s Vector Control Advisory Group.
The WMP intends to scale up the project. Earlier this year, the organization announced plans to build a factory in Brazil to produce modified mosquitoes to be released in many of the country’s urban areas over the next ten years. They still face challenges — for example, the strategy to deploy mosquitoes must be tailored to fit the geographical and social circumstances of each region. Some areas are harder to access than others, and community engagement with the project can vary.
Lalita Panicker is Consulting Editor, Views and Editor, Insight, Hindustan Times, New Delhi