No tetravalent influenza vaccine

influenza-vaccineTwo different influenza vaccines will be available in the fall of 2009. One will be a trivalent preparation comprising seasonal influenza H3N2 and H1N1 strains, plus an influenza B virus strain. A monovalent vaccine will also be available against the 2009 pandemic H1N1 strain. Many readers of virology blog have asked why these four virus strains will not be combined into a single, tetravalent formulation. I posed this question to Dr. Ruben Donis, chief of the molecular virology and vaccines branch at the U.S. Centers for Disease Control and Prevention. Here is his answer.

Some of the reasons that make tetravalent influenza vaccine less attractive at this time:

  • Regulatory considerations: there have been no clinical trials with tetravalent influenza vaccines, and there is little time to do them now. Licensing without data is not a favored option. However, clinical trials for a monovalent have been started and will help establish appropriate doses, formulations, in different population groups.
  • Public health considerations: the populations at greater risk of severe outcomes are not the same for the seasonal viruses and the H1N1 – pregnant women are high on the list for receiving H1N1 vaccine.
  • Timing considerations: Seasonal vaccine will be available in September whereas pandemic H1N1 vaccine will become available later.
  • Vaccine effectiveness, adverse events, pharmacovigilance: it will be easier to monitor vaccine performance characteristics using a monovalent

He also mentioned the possiblity of making a trivalent preparation with the pandemic H1N1 strain. But he said that

…a trivalent with pandemic H1N1 would entail eliminating one of the current seasonal viruses – we don’t have evidence that any of the three seasonal viruses is becoming extinct.

I thank Dr. Donis for responding.

TWiV 42: Bats and ticks

twiv-200Hosts: Vincent Racaniello, Dick DespommierAlan Dove, and Delthia Ricks

In episode #42 of the podcast “This Week in Virology”, Vincent, Dick, Alan, and Delthia Ricks discuss a new influenza virus-like particle vaccine, dog flu, ultrasensitive pen-sized virus detector, imported rabies in the US, Crimean-Congo hemorrhagic fever, and next season’s flu vaccines.

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Click the arrow above to play, or right-click to download TWiV #42 (40 MB .mp3, 58 minutes)

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Links for this episode:
Trivalent virus-like particle vaccine
Canine flu virus vaccine
Ultrasensitive virus detector
Rabies imported into the US
Crimean-Congo hemorrhagic fever in Kazakhstan
FDA approves seasonal flu vaccine for fall
Yields of 2009 H1N1 vaccine are low
FDA may fast-track approval of 2009 H1N1 vaccine

Weekly Science Picks
Delthia 100 questions and answers about influenza by Delthia Ricks
Vincent Effect Measure

Send your virology questions and comments (email or mp3 file) to or leave voicemail at Skype: twivpodcast

Influenza in the US, week 23

The Centers for Disease Control and Prevention has published their weekly analysis of influenza activity for the week of 7-13 June 2009. They conclude that

…influenza activity decreased in the United States, however, there were still higher levels of influenza-like illness than is normal for this time of year.

During week 23, 38.7% of specimens (2,765 out of 7,149) tested positive for influenza virus. Of these, 82% (2,263) were identified as the pandemic H1N1 strain. The H3N2 strain, and last season’s H1N1 strain, accounted for only 21 and 22 of the positive specimens, respectively. These results are shown in the following graph:


The numbers raise at least two questions. First, the seasonal H3N2 and H1N1 strains are clearly disappearing. Is this because it is the end of the influenza season in the northern hemisphere, a time when influenza typically drops to very low levels? Or is it because the older viruses are being ‘forced out’ by the new pandemic strain? The fact that the pandemic H1N1 strain is also supplanting last year’s strains in Australia suggests that these viruses will not return in the fall.

The other question is why the pandemic H1N1 strain continues to cause a significant number of infections in the northern hemisphere in June. We’ve previously discussed how temperature and humidity are believed to be important factors in determining the seasonal patterns of influenza in temperate climates. Clearly the 2009 pandemic strain isn’t following these ‘rules’. Neither did the 1918 pandemic strain. Could it be that seasonality of  influenza is regulated not only by temperature and humidity, but also by levels of population immunity? Perhaps, after a season of influenza, the high levels of immunity coupled with high temperatures and humidity together lead to reduced disease in the summer. Because population immunity to a pandemic strain is extremely low or nonexistent, the virus can circulate even in conditions of high temperature and humidity. This hypothesis is undoubtedly an oversimplification, and other factors, such as transmissibility, are also likely to play a role. For example, the pandemics of 1889, 1957, and 1968 did display seasonality in the northern hemisphere – see Figure 1 in the paper cited below.

Miller, M., Viboud, C., Balinska, M., & Simonsen, L. (2009). The Signature Features of Influenza Pandemics — Implications for Policy New England Journal of Medicine, 360 (25), 2595-2598 DOI: 10.1056/NEJMp0903906

Influenza surveillance in the US

A network of ~150 laboratories in the United States participate in virological surveillance for influenza. The results of these analyses are publicly available, and provide extremely interesting characterization of the pandemic spread of the new H1N1 strain. During week 22, 6,664 samples were submitted for testing, of which 2,681 were positive for influenza virus. Of these, 2,071 (89%) were identified as the new H1N1 strain. The previous seasonal influenza A (H1), A (H3), and B viruses continue to co-circulate. These observations are summarized on this graph:


I have noted previously the unusual upsurge in influenza activity during weeks 17 and 18, which coincided with the emergence of the new H1N1 virus. The number of virus-positive specimens dropped during week 19, but has since risen. More importantly, the percent positive specimens – the black line – continues to rise. This observation suggests that the new H1N1 virus will continue to circulate, at least for the next month. Increased sampling by clinicians in the face of a pandemic probably also contributes to the rising numbers of influenza positive specimens.

Also of interest is the declining circulation of the two influenza virus strains of the previous season – H3N2 and H1N1. Of the 2,681 influenza positive samples in week 22, 9 were identified as the previous seasonal H1N1 strain, and 22 as the H3N2 strain. The circulation of these seasonal influenza viruses into June is probably not abnormal. Because of the pandemic H1N1 strain, more samples are being tested than is usual. Clinicians stop testing for influenza virus at the end of May as the ‘flu season’ wanes. CDC stops its influenza surveillance in May, and resumes in the fall. This year CDC will probably keep up the influenza reporting through the summer. According to Dr. Anthony Fiore, a medical epidemiologist at CDC,

Now people who don’t normally look for flu are looking more than they ever have. We’re seeing that some of the respiratory illnesses that occur even late in the season may be due to seasonal flu viruses that we didn’t appreciate in the past. I guess we don’t know that anything different is occurring right now with seasonal flu viruses. This is an artifact of clinicians looking very hard for flu viruses at a time they don’t normally look.

The textbooks have always said that influenza viruses can be isolated from large northern hemisphere cities throughout the summer. The increased surveillance this year will provide a more detailed picture of the extent of influenza virus spread.

I’m also looking forward to reviewing influenza surveillance data from the southern hemisphere in the coming months. The Department of Health and Ageing of Australia provides similar data as the CDC, but their information has not been updated since 22 May and consequently the impact of circulation of the new H1N1 strain is not evident.

Co-circulation of three human influenza A subtypes

Although the new influenza H1N1 strain has been receiving a great deal of attention, apparently last season’s H1N1 and H3N2 strains continue to circulate, at least in the United States. FluView, the weekly surveillance report from the CDC, indicates that during weeks 17 and 18, seasonal influenza A (H1), A (H3), and B viruses are co-circulating with novel influenza A (H1N1). Half of all influenza viruses detected are the swine-like H1N1 viruses. The statistics are shown in this bar graph:


Seasonal influenza in the US peaked in week 6 (February) and declined by week 16. With the emergence of the new H1N1 strains, there came an upsurge in influenza activity during weeks 17 and 18.

Two aspects of these data are noteworthy. First, it is very interesting that influenza viruses of three different subtypes – H3N2, and two H1N1 – are circulating at the same time. On at least two previous occasions, the seasonal influenza strain was replaced by the new pandemic virus. In 1957, when the H2N2 strain emerged, it replaced the previously circulating H1N1 strain. Then in 1968, the H2N2 strain was replaced by the H3N2 strain. The reasons for the replacement of influenza virus strains during these two episodes of antigenic shift remain obscure. Should we expect the new H1N1 strain, if it goes on to be the pandemic strain, to replace previously circulating human influenza A viruses? When the H1N1 influenza virus re-emerged in 1977, it did not replace the H3N2 viruses – although it did not go on to be the next pandemic strain. Whether or not the new H1N1 viruses will dominate is anyone’s guess. Clues might come from which strains are isolated in the southern hemisphere in the coming weeks.

I am also intrigued by the observation that circulation of last season’s H3N2 and H1N1 strains, nearly over by week 16, has suddenly been revived along with introduction of the new H1N1 strain. Put another way, why is there a general upsurge in influenza cause by all three A subtypes? Perhaps it’s just an unusual outbreak late in the season, which has certainly happened in the past, only this time, there is a new virus thrown into the mix.

Influenza A/Mexico/2009 (H1N1) update

reassortment-swine-300x157Here is an update on the global swine flu situation as of 4 May 2009, and comments on interesting unresolved questions.

There have been laboratory confirmed cases of infection in over half of the United States (30), with a total of 226 cases and the one death in Texas last week. Globally, 20 countries have reported 985 cases of infection. The highest numbers are in Mexico, with 590 cases and 25 deaths.

According to CDC, very few of the American cases are in individuals who are over 50 years of age. This observation suggests that exposure to previous H1N1 strains might confer some protection against infection, as suggested by Dr. Peter Palese. Individuals who are over 50 today were born in 1959 or earlier. Recall that from 1918 to 1957, H1N1 influenza viruses circulated globally. Those who are older than 50 were likely to have been infected with H1N1 influenza virus strains during those years. Whether or not there is any protection from such previous exposure will likely be determined by laboratory tests in the near future.

Also very interesting is the report from Alberta, Canada that pigs have been infected with the human H1N1 virus. It is believed that the animals were exposed to the virus by a Canadian who had returned from Mexico with flu-like symptoms. This report raises more questions than it answers. But if the new H1N1 virus can readily infect pigs, this could serve as a new source of the virus for future outbreaks. Promedmail poses the tough but important questions:

First, how was directionality of infection established? Was the worker sick when he came in contact with pigs? If so, what lapse in biosecurity allowed a sick human worker to even be on a swine farm as standard biosecurity practices on progressive or up to date swine farms would screen such an individual out and prevent him or her from coming into contact with pigs? Has the worker tested positive for the novel influenza A H1N1 virus? What is the prevalence of the new virus in the swine herd and finally, but most importantly, what quarantine and traceback procedures are in place to make sure that the swine herd does not infect other swine farms? Finally, although we know animal diagnostic laboratories have never seen this virus before in pigs, what surveillance efforts are being made to look at previous swine serum banks or test apparently healthy swine herds on a population basis to actively ensure swine populations are free of this novel influenza A H1N1 virus?

Another important question concerns influenza vaccines. According to Health and Human Services Secretary Kathleen Sebelius, vaccines for the new strains, as well as last season’s, will be ready this fall. Clearly we need a vaccine containing the new H1N1 strain and the relevant influenza B virus strain. But what about last season’s strains – there were two, an H1N1 and an H3N2. If these were also included, that would make for a tetravalent influenza virus vaccine.

Here is one bit of information which would argue against including last year’s H3N2 and H1N1 strains in this fall’s vaccine. In each previous pandemic, the newly emerging viruses replaced the previous circulating strain. For example, in 1968, the H3N2 virus replaced H2N2 viruses that had been causing influenza since 1957. Whether or not the new H1N1 viruses replace the two previous strains will be an important question to address in the coming months. Such information will be used to make decision about the components of the influenza virus vaccine used this fall.

Update: terrific map from WHO on laboratory confirmed cases.


Oseltamivir resistance in current H1N1 influenza virus strains

397723615_3493f379cb_mThe CDC has issued a health advisory which indicates that a high number of currently circulating H1N1 influenza viruses are resistant to the antiviral drug oseltamivir. Fifty H1N1 isolates obtained in the U.S. since October 2008 were examined for drug sensitivity; 98% of these isolates are resistant to oseltamivir. Influenza H3N2 isolates, however, are still susceptible to the drug.  The H1N1 isolates remain sensitive to zanamivir and amantadine. As a result of this finding, the CDC suggests that for treatment of influenza, “zanamivir or a combination of oseltamivir and rimantadine are more appropriate options than oseltamivir alone.”

Oseltamivir and zanamivir are recently developed influenza antiviral drugs that inhibit the viral neuraminidase. This enzyme is required for infection and spread, and consequently its inhibition reduces viral production and disease. Both inhibitors were designed to mimic the natural ligand of neuraminidase, sialic acid. In theory, the more an inhibitor resembles the natural compound, the less likely the target can change to avoid drug binding while maintaining viable function. The results with oseltamivir do not support this theory. During the 2007-08 influenza season, 10.9% of H1N1 viruses tested in the U.S. were resistant to the drug. Although it is not known what percentage of the 2008-09 isolates will be resistant to oseltamivir, it is clear that resistance to this drug is rising.

It is not surprising to observe increasing resistance to oseltamivir, given the high mutation rates of RNA viruses. What is somewhat surprising is the absence of resistance to zanamivir. This difference may be in part due to structural differences between the two compounds – perhaps it is more difficult for the neuraminidase to be resistant to zanamivir and still have enzymatic function. The ways that the drugs are administered may also play a role – oseltamivir is taken orally, a route that is more widely accepted, while zanamivir is given by inhaler. Consequently, it is probably used less than oseltamivir.

One consequence is probably certain: the CDC recommendation that the two neuraminidase inhibitors be used in combination this year is likely to increase resistance to both neuraminidase inhibitors. This will be a difficult problem because there is widespread resistance among H3N2 strains against the only other licensed anti-influenza virus drug, the amantadines.