By Maggie Fox

WASHINGTON (Reuters) Nov 20 - As US health officials struggle to vaccinate tens of millions of Americans against the pandemic of swine flu, some are looking regretfully at one easy way to instantly double or triple the number of doses available: using an adjuvant.

These additives, often as simple as an oil and water mixture, broaden the body's response to a vaccine, reducing the amount of antigen needed.

Adjuvants are widely used in European flu vaccines as well as in Canada. But not in the United States -- even though the federal government has spent nearly $700 million buying them.

The reason -- people might not trust them.

"If we really do want pregnant women to trust this vaccine or even parents, we have to think about what is acceptable to them," Dr. Anne Schuchat of the US Centers for Disease Control and Prevention said in an interview.

"We have so much vaccine hesitancy in this country," agreed Jeff Levi of the non-profit Trust For America's Health. "To add...a new element could well have undermined the efficacy of this campaign," Levi told a hearing this week before a Congressional subcommittee.

This frustrates the World Health Organization, which says the global capacity to make influenza vaccines is about 3 billion doses a year -- not enough to cover the population of 6.8 billion people. WHO has hoped rich countries would donate leftover H1N1 vaccine to others.

The US Health and Human Services Department was ready to try adjuvants had the pandemic been worse. The H1N1 virus has infected an estimated 22 million Americans and killed 3,900, but it so far does not appear to be any deadlier than seasonal influenza.

The worry is that it is affecting younger adults and children instead of the elderly usually targeted by flu, and has the potential to mutate into something more deadly.

"If things had been worse and this would have been a more severe pandemic, we may well have needed to go that way anyway," Levi said.

Instead, the US has stuck with what CDC director Dr. Thomas Frieden has repeatedly called the "tried and true" approach -- the same formulation used in seasonal flu vaccines. Five companies have contracts -- Sanofi-Aventis, CSL, Novartis, AstraZeneca unit MedImmune and GlaxoSmithKline.

Polls show that only about half of Americans plan to be vaccinated against H1N1. Of those who do not, about half say they worry about safety.

Even so, long lines have formed as people try to get the 50 million or so vaccine doses that have rolled out of factories. Drug companies have struggled with an unpredictable virus that does not grow well in eggs, as well as changes to US orders that slowed down packaging.

Studies suggest the supply that is out now could have been tripled.

In September, GlaxoSmithKline found a single shot of its H1N1 vaccine protected 98% of volunteers, using an adjuvant and just 5.25 micrograms of antigen. A standard dose without adjuvant uses 15 micrograms of antigen.

Vaccine makers urged Congress this week to help federal agencies find ways to approve the use of adjuvants, and to assure skeptical Americans about their safety.

Dr. Vas Narasimhan, president of Novartis Vaccines USA, noted adjuvants had been licensed for use in Europe for 10 years and tested in 200,000 people.

"Adjuvanted vaccines produce higher immune response than unadjuvanted vaccines, particularly in the elderly and young children," Narasimhan told a hearing this week.

He said they may protect better than standard vaccines against viruses that have drifted a little -- the single biggest reason that flu vaccines must be re-formulated every year.

They may also eventually help require less vaccination. "Adjuvanted vaccines have been shown to more broadly prime patients' immune response -- up to seven years later -- requiring fewer vaccinations to the newly circulating strain," he said.

The National Institute of Allergy and Infectious Diseases is intrigued. Last month it awarded $60 million to researchers and companies to develop new adjuvants

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Atlanta, Georgia (CNN) -- As H1N1 cases are rising, so are bacterial pneumonia cases, health officials are finding.

They're seeing an increase in flu complications leading to pneumonia. At the same time, the flu is at record levels because of the new H1N1 virus, also known as swine flu.

The number of cases is outpacing the typical number of regular flu cases at this time of year. Cases of regular flu usually peak between December and May.

"We're seeing an increase in serious pneumococcal infectious around the country," said Dr. Anne Schuchat, who heads the National Center for Immunization and Respiratory Diseases at the Centers for Disease Control and Prevention.

The CDC tracks pneumococcal infections with help from 10 state health departments.

For instance, Denver, Colorado, averages about 20 cases of pneumonia in October during a regular flu season, Schuchat said. But "in October 2009, they had nearly triple that number."

The Denver area has seen 58 flu-related pneumonia cases, and at least two-thirds of those sickened were aged 20 to 60, she said.

During a regular flu season, most serious cases of flu and flu-related pneumonia occur in people 65 or older. However, people younger than 65 are much more vulnerable to H1N1, because the virus is unlike any other flu their bodies have come in contact with.

A flu infection thins the lining of the respiratory tract, making the lungs more vulnerable to bacteria that can cause pneumonia.

CDC officials are urging high-risk adults to get vaccinations against both pneumonia and H1N1.

Smokers and people with diabetes; chronic heart, lung and liver disease; or HIV are considered high-risk.

Only 25 percent of high-risk adults under age 65 have gotten a pneumonia vaccination, Schuchat said at a news briefing Wednesday.

"It's a vaccine you pretty much get once as an adult, not every year, the way the flu vaccine works," she said.

The CDC also announced that 7 million more doses of H1N1 vaccine have been made available since Friday, bringing the total doses available so far to 61.2 million.

CDC officials have studied safety data since H1N1 vaccinations started in early October.

"So far, everything we've seen is very reassuring," Schuchat said. " ... we're seeing patterns that are pretty much exactly what were seeing with the seasonal flu vaccine."

Most of the reported side effects include sore arms and tenderness at the injection site.

Health officials are particularly interested in a side effect that can cause a rare neurological illness called Guillain-Barre syndrome, because the last time a large-scale pandemic vaccination program was launched, in 1976, there was an alarming rise in Guillain-Barre cases.

This time, after millions of Americans have been vaccinated, Schuchat said, only 10 potential cases of Guillain-Barre have been reported, which is similar to what health officials see during a regular flu season.

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Published at www.nejm.org November 25, 2009 (10.1056/NEJMp0910445)

James F. Bishop, M.D., Mary P. Murnane, B.A., and Rhonda Owen, B.Sc.

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When the World Health Organization declared a "public health emergency of international concern" on April 25, 2009, after the emergence in Mexico of pandemic influenza A (H1N1) virus, Australia activated its well-rehearsed plan for response to pandemic influenza.¹ The Australian Health Management Plan for Pandemic Influenza is a strategic outline, based on evidence and international best practices, of actions and interventions that the health care community should consider taking during a pandemic. It describes the planning assumptions, the phases of a response, and the key actions that minimize a pandemic's effects on the population and the health care community. Over the subsequent 6 weeks, the implementation of border-control measures — including requirements that travelers entering Australia declare whether they have symptoms of influenza or have been in contact with someone with severe respiratory illness and that contacts of persons with known influenza be traced — gave the health care community time to learn more about the natural history of the new influenza strain.²

The groups that had been identified worldwide as the most vulnerable to poor outcomes were pregnant women, indigenous populations, and persons with gross obesity or serious underlying medical conditions. Australia pursued a modified version of its national plan for pandemic influenza, under which such persons and those with rapidly progressing influenza and respiratory distress were targeted for early outpatient-based treatment with antiviral medication and careful follow-up by primary care physicians and hospitals. Additional public health mitigation measures included opening the national stockpile of antiviral medication, providing personal protective equipment to general practitioners, issuing public messages recommending self-quarantine at home for persons with influenza-like illness, and launching public-awareness campaigns aimed at reducing droplet spread of the disease.

This first wave of 2009 pandemic influenza A (H1N1) virus infection lasted about 18 weeks in Australia, from mid-May to late September 2009 (see graph).³ Consultations for influenza-like illness in general practices and emergency departments peaked at 34 and 38 per 1000 consultations, respectively. The percentage of clinical isolates that tested positive for influenza A peaked at 38 to 65% in the various states and territories, and the 2009 H1N1 virus accounted for 90% of influenza A isolates by week 8 (see maps). Rates of absenteeism from work and school were similar to those seen in 2007, the year in which Australia had its worst recent influenza season. The rate of hospitalizations was 23 per 100,000 population, with indigenous Australians overrepresented (16%) and about 13% of all patients who were hospitalized being admitted to intensive care units (ICUs). The highest rate of hospitalization occurred among children under 5 years of age. Boys younger than 5 years of age were hospitalized at rate of 67.9 per 100,000 population, and girls in that age group at a rate of 54.1 per 100,000 population, as compared with 51.1 per 100,000 population in this age group during previous influenza seasons. The median length of stay was 3 days, with 19% of patients being hospitalized for more than 7 days.

View larger version (28K): [in this window] [in a new window] The Geographic Spread of the 2009 Influenza A (H1N1) Virus in Australia. Data are from the Australian Influenza Surveillance Reports.

View larger version (38K): [in this window] [in a new window] The Frequency of Laboratory-Confirmed 2009 Influenza A (H1N1) Virus Infection in Australia. Data are from the Australian Influenza Surveillance Reports and are organized according to statistical divisions defined by the Australian Bureau of Statistics; an area under the unifying influence of one or more major towns or cities constitutes a statistical division.

Intensive care specialists identified some patients with confirmed 2009 influenza A (H1N1) virus infection and "lung-only" single-organ failure whose lung function could not be sustained with the use of ventilators. Among these patients, extracorporeal membrane oxygenation (ECMO) was used extensively.⁴ Approximately 2.1 patients per million population were treated with ECMO, and two thirds of these patients survived.

A distinguishing feature of the epidemic was the number of people who were hospitalized in ICUs with confirmed cases of pandemic H1N1 influenza (3.5 per 100,000) and their young age (median, 42 years). According to data from influenza reports and from the Australian government, a total of 387 adults (over 20 years of age) were admitted with viral pneumonitis resulting from influenza A, as compared with a median of only 57 adults per year admitted with viral pneumonitis from any cause between 2005 and 2008. The peak of the epidemic in Australia lasted about 3 weeks, and although the Australian health system was stressed, there was spare capacity of ECMO equipment, hospital beds, and ICU beds.

Before the 2009 H1N1 virus reached Australia, there were dire predictions that the country would see many thousands of deaths from infection with this virus. In reality, 190 deaths associated with the virus have been confirmed to date, although some additional cases may not have been documented. A broader measure of all Australian deaths resulting from influenza or pneumonia currently indicates that there have been fewer such deaths than in other influenza or winter seasons.³ However, this year the median age of the patients who died was 53 years, as compared with 83 years in previous seasons. The lower-than-expected number of deaths could reflect the success of public health mitigation measures, the use of early antiviral therapy against a sensitive virus, and the natural history of this illness, which tends to be moderate in most people rather than severe.

A national vaccination program was begun in Australia on September 30, 2009, using a monovalent, unadjuvanted 2009 influenza A (H1N1) vaccine (Panvax, CSL Biotherapies).⁵ In clinical trials of this vaccine, Australian participants had higher than expected levels of protective cross-reactive antibodies, although the implications of this finding are uncertain. It is possible that more asymptomatic infections had already occurred. This vaccination program should provide a higher level of protection for the Australian population against an anticipated second wave of infection with the virus.

Key lessons so far from this experience in an unprotected population suggest that important elements of the response were a national coordination of efforts and the use and modification of the national pandemic plan framework, focusing on persons who were most at risk. The spread of the epidemic occurred earlier in some geographic locations than in others, which created challenges (such as implementing the school closure policy) in terms of maintaining a coordinated national approach to the epidemic. This challenge was addressed in part by holding regular meetings of the cross-jurisdictional Australian Health Protection Committee. Public messages regarding the public health response used the names of the phases of the pandemic plan, including "Delay," "Contain," and "Protect," which may have helped the public to take appropriate personal action and reduce the impact of the virus on our population.

Financial and other disclosures provided by the authors are available with the full text of this article at NEJM.org.

Source Information

From the Department of Health and Ageing, Canberra, ACT, Australia.

This article (10.1056/NEJMp0910445) was published on November 25, 2009, at NEJM.org.

References

1. Australian health management plan for pandemic influenza. Canberra: Australian Government Department of Health and Ageing, 2008.
2. Shinde V, Bridges CB, Uyeki TM, et al. Triple-reassortant swine influenza A (H1) in humans in the United States, 2005-2009. N Engl J Med 2009;360:2616-2625. [Erratum, N Engl J Med 2009;361:102.] [Free Full Text]
3. Australian Government Department of Health and Ageing. Australian influenza surveillance report no. 21: reporting period 26 September–2 October 2009. (Accessed November 20, 2009, at http://www.healthemergency.gov.au.)
4. The ANZIC Influenza Investigators. Critical care services and 2009 H1N1 influenza in Australia and New Zealand. N Engl J Med 2009;361:1925-1934. [Free Full Text]
5. Greenberg ME, Lai MH, Hartel GF, et al. Response after one dose of a monovalent influenza A (H1N1) 2009 vaccine — preliminary report. N Engl J Med 2009;361. DOI: 10.1056/NEJMoa0907413.

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