Cambodian study hints at subclinical H5N1 cases

Jan 25, 2008 (CIDRAP News) – A recent study in Cambodia suggests that some human cases of infection with the H5N1 avian influenza virus escape detection because symptoms are mild or absent, according to a report from an international avian flu conference this week in Bangkok.

The meeting drew about 500 experts from 40 countries to discuss research and ideas on a wide range of topics. Some other topics discussed included the idea of stockpiling vaccine adjuvants to prepare for a pandemic, the use of engineered human antibodies as a defense against the H5N1 virus, and the high H5N1 case-fatality rate in Indonesia.

Cambodian study
The Cambodian researchers tested 674 people in two villages who were exposed to the virus and found that seven of them, all between the ages of 4 and 18, had antibodies signaling previous infection, according to a Jan 24 Bloomberg News report.

The finding contrasts with previous serologic studies of people in areas affected by H5N1 outbreaks. A review published Jan 16 in the New England Journal of Medicine (NEJM) said the few serologic studies since 2003 of people with potential exposure to H5N1 suggest that asymptomatic or mild cases are rare. The studies involved people living with backyard poultry, workers in live-bird markets, and healthcare workers.

More cases of mild disease might suggest that the virus is improving its ability to spread among humans, while becoming less virulent. Based on the current global count of 353 cases with 221 deaths, the case-fatality rate is almost 63%.

The Cambodian researchers, led by Sirenda Vong of the Pasteur Institute of Cambodia in Phnom Penh, conducted their study in early 2006, according to the Bloomberg story. The researchers asked villagers about their exposure to poultry and tested their blood for antibodies to H5N1.

The median age of the seven people who had antibodies was 12 years, compared with 27 years for those who had no antibodies, the story said.

Vong and colleagues had conducted a similar study of 351 Cambodian villagers in 2005 and found that none had antibodies to the virus. The study was published in Emerging Infectious Diseases in 2006.

Malik Peiris, a microbiology professor at the University of Hong Kong, told Bloomberg that the latest study supports findings from the 1997 H5N1 outbreak in Hong Kong, in which human cases were first reported. The virus infected 18 people, 6 of whom died. Peiris said children were less severely affected than adults and had a better survival rate, Bloomberg reported.

"Most of the children diagnosed in Hong Kong in 1997 had a very mild course of infection; they basically had a mild flu-like illness and they recovered," Peiris was quoted as saying. "I don't think there is any evidence to say the situation has changed."

The recent NEJM review said H5N1 infections involving febrile upper respiratory illnesses without pneumonia in children have been reported more often since 2005, but early antiviral treatment may account for this.

Stockpiling of adjuvants
Another topic raised at the meeting was the idea of separately stockpiling adjuvants, immune-boosting chemicals that enable vaccine producers to reduce the dose of antigen in a vaccine without reducing immune response. Global health officials, including those at the World Health Organization (WHO), hope this dose-sparing approach could dramatically increase the world supply of pandemic vaccine.

Albert Osterhaus, a virologist at Erasmus Medical Center in the Netherlands who spoke at the conference on Jan 23, said stockpiling adjuvants would be useful if the pandemic strain turned out to be a subtype other than H5N1, according to a Jan 23 Reuters report.

"There's a lot of discussion to vaccinate people against H5N1 with adjuvanted vaccines," Osterhaus said. "We might do that, but it's very expensive and it might well be that the pandemic outbreak may not be caused by H5N1 but by H7, H9, or H2 [viruses]."

Osterhaus said adjuvants should be stockpiled separately from antigens, Reuters reported. "Adjuvants can be stockpiled and H5 antigen as well," he said. "So if the pandemic is going to be H5N1, you just mix them and you get a vaccine. If not, you rapidly produce the antigen and add it together with the adjuvant."

Currently, the United States has no licensed influenza vaccines that contain adjuvants, according to a previous CIDRAP News report. However, a few studies of influenza vaccines with alum-based adjuvants have shown acceptable protection levels. In August, researchers working on a GlaxoSmithKline vaccine reported positive results for a split-virus vaccine combined with a proprietary oil-and-water adjuvant. A month later, Sanofi Pasteur reported promising results for its inactivated vaccine paired with its own adjuvant.

Using engineered antibodies
In other developments, a researcher from Crucell, a Dutch biotechnology company, reported at the conference today that engineered human monoclonal antibodies to the H5N1 virus protected mice from several strains of the virus, according to a Reuters report.

Crucell created the human antibodies by mixing antibody fragments taken from nine blood donors with antigens from two H5N1 strains found in Vietnam and Indonesia, Reuters reported.

Mark Throsby, project director for antibody discovery at Crucell, told the conference that in vitro studies showed that one line of the engineered antibodies neutralized several strains of the H5N1 virus, including strains isolated in Hong Kong in 1997, Indonesia in 2005, and Vietnam in 2003, Reuters reported.

In the animal studies, he said, researchers injected the engineered antibodies into mice that had been given normally lethal doses of H5N1 virus 3 days earlier. "We were able to protect all the animals," Throsby was quoted as saying. "It reduced their disease and they became well again."

Drug resistance in Indonesia?
Yesterday Menno de Jong, a virologist at an Oxford University clinical research unit in Ho Chi Minh City, Vietnam, spoke on the topic of drug failure in the treatment of patients who have H5N1 infections. The case-fatality rate for the disease in Indonesia is especially high—82%, compared with about 63% overall, based on WHO figures.

De Jong told the conference that researchers are conducting studies to see if H5N1 patients in places like Indonesia, Thailand, and Vietnam require higher doses of antiviral medications, Reuters reported yesterday.

"It could be they are treated later, or the virus is different, more virulent," de Jong told a Reuters reporter. "There are many maybes, including differences in the susceptibility of the virus."

He told Reuters that the H5N1 viruses in Indonesia appear less susceptible to osteltamivir, the antiviral recommended as first-line treatment for H5N1 infections. "It's not a resistant virus, it's just that a bit more drug [may be] needed to inhibit these [H5N1] clade 2 viruses," he said.

De Jong was a member of the WHO expert panel that wrote the recent review in the NEJM on human H5N1 cases. In line with de Jong's observations at the Bangkok meeting, that article said clade 1 viruses appear to be 15 to 30 times more susceptible to oseltamivir than clade 2 viruses from Turkey and Indonesia. However, the panel wrote that the clinical relevance of this difference in oseltamivir susceptibility "remains to be determined."

See also:

Jan 16 CIDRAP News story on NEJM review of human H5N1 cases: "Exposure source unclear in 25% of H5N1 cases"

Sep 7, 2006, CIDRAP News story "Cambodian study suggests mild H5N1 cases are rare"

Oct 30, 2007, CIDRAP News story "The Pandemic Vaccine Puzzle, part 4: The promise and problems of adjuvants"

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