Primecuts-This Week in the Journals

December 22, 2009

trainIshmeal Bradley, MD

The year 2009 could aptly be named “The Year of the Swine Flu.” Indeed, the emergence of a new influenza pandemic was the biggest health story of the year. In a rather tongue-in-cheek approach, the journal Science named the new H1N1 strain “Virus of the Year.” (1) While the public health community had been focused on Asia as the source of the next great influenza pandemic, especially given the outbreak of H5N1 avian flu in 2003, H1N1 surfaced unexpectedly in North America. The virus, discovered in Mexico in March, quickly spread around the world. Then, on June 11, 2009, the World Health Organization declared a state of pandemic. As of last week, 28 countries had reported cases of H1N1 with an estimated death toll of 9,600 people worldwide.

Quickly after the appearance of this new virus, researchers began to the race to develop a vaccine. Since the virus appeared in the North American spring, drug manufacturers wanted to create a vaccine before the start of the autumn flu season. Both the New England Journal of Medicine and the Annals of Internal Medicine published articles on H1N1 vaccine trials at various sites worldwide. Some of the key questions in these three trials focused on the optimum dose of vaccine and whether multiple doses would be needed (especially for children and the elderly). Another article examined the cost effectiveness of a large scale vaccination program in a city the size of New York.

The first of these trials is a study out of England. (2) In this study by Clark et al., they tested an oil-in-water adjuvanted H1N1 vaccine at a single center in Leicester, England. This was a small, randomized, phase 1 study with only 176 patients. The researchers compared different doses of non-adjuvanted vaccine with different doses of adjuvanted vaccine, both given over the course of three weeks, to determine which dose would elicit the best immune response. One purpose of their study was to find out if an accelerated vaccination schedule (i.e. a single dose rather than two dose spread out over one to three weeks) would be sufficient to create immunity. They found that a single dose of adjuvanted H1N1 vaccine at 15µg would be sufficient. This study had several drawbacks, however, notably its inclusion only of adults aged 18-50 years old and its very small sample size. Since children and the elderly are the most vulnerable to influenza, data on these age groups would have been welcome.

These English results were echoed in a study out of Australia. (3) Greenberg et al. wanted to study which was the optimum dose of vaccine and if the elderly would benefit from multiple doses. Over the summer there was significant uncertainty in the medical community about the effect of age on the immune response. This larger, phase 2 study (240 patients) was randomized, observer-blind, and had four arms: subjects aged 18-49 with low-dose vaccine, 18-49 with high-dose vaccine, subjects aged 50-64 with low-dose vaccine, and 50-64 with high dose vaccine. Again, children and adolescents were excluded from this study. Each patient received a non-adjuvanted vaccine (either 15 or 30µg) 21 days apart. They observed that after a single low-dose vaccine, there was a 77% seroconversion rate for those aged 18-49, compared with a 71% conversion rate for those 50-64. After a single high-dose vaccine, there was an 85% conversion rate for those 18-49, compared with 77% for those 50-64. After a second dose, these seroconversion rates increased to 84% and 81% for the low-dose group and 88% and 91% for the high-dose vaccine group. Their results provided more information that a single dose of 15µg of H1N1 vaccine was adequate to protect most adults. Given the initial concerns that there would be a profound vaccine shortage, their study shows the vaccine supply could be stretched to cover more people if only one dose per person was used.

The last vaccine study comes from China. (4) This mammoth trial by Zhu et al. enrolled 2,200 patients in Taizhou, China, and it was more encompassing than the previous two studies. Their goal was to determine if certain age groups, namely the very young and very old, would mount an appropriate immune response after one dose of vaccine, or if a booster would be needed as data from other studies had suggested. In addition to the sheer size of this study, two other strengths are the remarkably high follow-up numbers (94% of subjects were included in the final analysis) and its focus on different age groups. These researchers stratified patients into four groups: children (3-11yo), adolescents (12-17yo), adults (18-60yo), and the elderly (+61yo). They also compared alum-adjuvanted vaccine with non-adjuvanted vaccine. Their data showed that the non-adjuvanted vaccine worked better than the adjuvanted one in creating immunity.

Briefly, they found that in the children group, 83% seroconverted after a single high-dose vaccine (30µg), compared with 75% in the low-dose group (7.5µg). After the second dose, both those in the high- and low-dose groups had a >95% conversion rate. For the adolescents in both the high- and low-dose groups, after a single shot, there was a 97% conversion rate, which increased to 100% after the second dose. In the adult group, there was >93% seroconversion after a single administration of either high- or low-dose vaccine. After the second dose, the conversion rate increased to >97%. And finally, in the elderly group, 79% converted after a single low-dose vaccine and 84% with the high-dose. After a second administration, these rates increased to 93% in the low-dose group and 96% in the high-dose group.

Age was an important factor in the immune response generated. Children and the elderly did not have as robust a response as adolescents or adults. However, after the second dose, they did reach >90% conversion. It also showed that since adolescents and adults mounted a significant response after one dose, a second dose did not substantially offer more benefit. This could affect public health policy by requiring the elderly and children to receive two doses, and offering only one does to adolescents and adults, thus saving much-needed vaccines for those in more need.

The benefit of these studies is that they give us valuable information about who should be vaccinated first and who would need repeat vaccinations. During a pandemic, it is crucial to know which citizens will need repeat vaccinations and at what dosing intervals to prevent catastrophic spread of a contagious disease. One more study from the Annals looks at the effectiveness and cost-effectiveness of a widespread vaccination campaign in the city the size of New York. (5) In their complicated statistical model, this team of public health researchers concluded that an early, widespread campaign would be cost-saving. If the pandemic peaked in October, then a vaccination campaign would save the city about $469 million if they assumed moderate infectivity, and $302 million if the pandemic peaked in November. Also, vaccinating the population in October would prevent 2,051 deaths compared with 1,468 deaths if the campaign started in November. A key finding of their model was that not everyone needed to be vaccinated in a pandemic. They found that only 40% of the population needed to be vaccinated to create herd immunity and limit viral transmission. This finding is important given the early limited supply of vaccines.

These four studies all assumed a relative paucity of available vaccine, which is not a trivial matter in a global pandemic. But thanks to the accelerated efforts by drug manufacturers, the American public will have many more vaccines than originally anticipated, about 100 million doses, the New York Times reported. (6) No longer is the vaccine restricted to high-risk patients (pregnant women, seniors, and those with chronic illnesses). Despite the high numbers of people who have already been vaccinated, the CDC is still recommending that more people get the shot to prevent a third wave of illness, especially now that more doses are available.

So, what should we be doing? It’s not too late to offer the vaccine to everyone, regardless of age, that comes into our office. There may have been a lot of hype earlier this year about the threat of pandemic, but thanks to the swift action of public health authorities, with quarantines and the rapid development of vaccines, it appears that much of that threat has remained unrealized. H1N1 may not have turned out to be great pandemic, but we did get valuable first-hand experience in preparing for the next big one.


1. Enserink, Martin and Jon Cohen. Virus of the Year: the Novel H1N1 Influenza. Science. 2009;326:1607.

2. Clark, T.W. et al. Trial of 2009 Influenza A (H1N1) Monovalent MF59-Adjuvanted Vaccine. NEJM. 2009;361:2424-35.

3. Greenberg, M.E. et al. Response to a Monovalent 2009 Influenza A (H1N1) Vaccine. NEJM. 2009; 361:2405-13.

4. Zhu, F.-C. A Novel Influenza A (H1N1) Vaccine in Various Age Groups. NEJM. 2009;361:2414-23.

5. Khazeni, N. et al. Effectiveness and Cost-Effectiveness of Vaccination Against Pandemic Influenza (H1N1) 2009. Annals of Internal Medicine. 2009;151:829-839.

6. Associated Press. More Vaccine Has US Urging Swine Flu Shots for All. New York Times [internet]. 2009 Dec 17.

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