TWiV 403: It’s not easy being vaccine

The TWiV team takes on an experimental plant-based poliovirus vaccine, contradictory findings on the efficacy of Flumist, waning protection conferred by Zostavax, and a new adjuvanted subunit zoster vaccine.

You can find TWiV #403 at, or listen below.

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TWiV #356: Got viruses?

On episode #356 of the science show This Week in Virology, Stephanie joins the super professors to discuss the gut virome of children with serious malnutrition, caterpillar genes acquired from parasitic wasps, and the effect of adding chemokines to a simian immunodeficiency virus DNA vaccine.

You can find TWiV #356 at

TWiV 217: I just flu in and my arms are shot

On episode #217 of the science show This Week in Virology, Vincent, Alan, Rich, and Dickson review influenza vaccines.

You can find TWiV #217 at

TWiV 211: Viruses r us

On episode #211 of the science show This Week in Virology, the TWiV four discuss an mRNA-based influenza vaccine, and a phage tubulin that forms a filamentous array in the host cell that is needed for positioning viral DNA.

You can find TWiV #211 at

TWiV 103: Shots with LJ Tan

Hosts: Vincent Racaniello, Alan Dove, and LJ Tan

On Episode 103 of the podcast This Week in Virology, Vincent and Alan discuss influenza vaccines with LJ Tan of the American Medical Association.

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Weekly Science Picks

Alan – BioGene, an iApp
Vincent – The Vertical Farm by Dickson Despommier

Send your virology questions and comments (email or mp3 file) to or leave voicemail at Skype: twivpodcast. You can also post articles that you would like us to discuss at and tag them with twiv.

Novartis influenza A H1N1 vaccine clinical data

influenza-vaccineAlthough the influenza 2009 H1N1 vaccine produced by Novartis, Fluvirin, was previously approved for use in the US, the clinical data supporting its safety and immunogenicity had not been released. The company has now issued a media release containing interim clinical data on the effects of the vaccine in humans.

According to the company, testing of the vaccine in 4,080 adult and elderly (>65 years) US individuals has revealed that a half dose (3.75 micrograms) without adjuvant “fulfilled immune response criteria associated with protection”. I assume that the latter statement means that hemagglutination inhibition titers of 1:40 or greater were observed, but this is not explicitly stated.  Current US guidelines for the 2009 H1N1 2009 vaccine stipulate that adolescents, adults and the elderly should receive one 15 microgram dose, and children 9 years of age and under are required to receive two 15 microgram doses four weeks apart.

Fluvirin with MF59 adjuvant was also tested in children ages 3 to 8, adults ages 18 to 64, and the elderly. The results indicate that a single 3.75 microgram dose of vaccine with adjuvant induced protective levels of immunity. The media release includes the following:

Novartis proprietary MF59 adjuvant has an established safety profile, supported by more than 12 years of clinical safety data and more than 45 million doses of commercial use in Europe. The adjuvant has been studied in clinical trials involving more than 33,000 people, including children, and has been licensed for use in people 65 years of age and over in the seasonal influenza vaccine Fluad® since 1997 in the European Union. Novartis also produces two A(H1N1) vaccines, Focetria® and Celtura®, which contain MF59 and are available outside the US.

MF59 adjuvant contains squalene, polyoxyethylene sorbitan monooleate (Tween 80) and sorbitan trioleate. No vaccine containing this adjuvant has been approved for use in the US.

A media release is no substitute for revealing clinical trial results in a peer-reviewed scientific journal. Novartis indicates that the vaccine trial will be completed in December 2009, and the results should be published shortly thereafter. It’s important for vaccine manufacturers to make clinical trial data freely available to address the concerns of those who are worried about vaccine safety.

GlaxoSmithKline influenza H1N1 vaccine approved

influenza-vaccineGlaxoSmithKline’s inactivated 2009 influenza H1N1 vaccine has been approved by the US Food & Drug Administration and by Health Canada. This action completes the list of pandemic H1N1 vaccines which I previously summarized for the US and Canada.

Influenza A (H1N1) 2009 monovalent vaccine is produced by ID Biomedical Corporation of Quebec, a wholly-owned subsidiary of GlaxoSmithKline. The US package insert can be found here (pdf) and the Canadian package insert here. Dosing recommendations for Canada are listed here. Health Canada has also posted a FAQ on the H1N1 vaccine.

The ID Biomedical vaccine is available only in multi-dose vials which contain thimerosal. Each 0.5 ml dose contains 15 micrograms of viral antigen. Other components of the vaccine listed at Health Canada include ‘trace amounts of egg proteins, formaldehyde, sodium deoxycholate and sucrose’. The presence of these compounds reflects how the vaccine is produced: the viral strain is propagated in chicken eggs, purified by centrifugation on sucrose gradients, inactivated with formaldehyde, and disrupted with sodium deoxycholate.

The vaccine has been tested in healthy adults but not in the elderly, adolescents, or children. Approval by both the US and Canada was based on the data from testing of the H1N1 and seasonal influenza vaccines, which are made by an identical process.

In healthy adults, the 2009 H1N1 vaccine produced the typical range of side effects, including pain at the injection site, redness, fatigue, and headache. Twenty-one days after injection of a 15 microgram dose, 93.9% of 66 adults produced an immune response, defined as a hemagglutination-inhibition titer of 1:40 or greater (which correlates with protection against infection). Only slightly higher seroconversion rates (97% of 66 adults) were observed when 21 micrograms of antigen were injected. Clinical trials are ongoing in North America, Europe, and Japan.

The GlaxoSmithKline vaccine is now available in Canada, but is not expected to ship to the US until December.

Influenza H1N1 vaccine approved in Canada

arepanrix-h1n1The influenza A (H1N1) 2009 vaccine produced by GlaxoSmithKline has been approved by Canada Health. Here is some information on the vaccine to supplement what I’ve provided about the US counterparts.

The Canadian vaccine, called Arepanrix H1N1, is supplied in two parts. One contains inactivated H1N1 influenza virus, and the second consists of AS03 adjuvant (DL-a-tocopherol, squalene, polysorbate 80). Before injection the virus and adjuvant are mixed. The vaccine is provided in 10-dose vials and therefore contains thimerosal. More information on the amounts of these components can be found at the Canada Health website (“Product Information Leaflet Arepanrix™ H1N1 AS03-Adjuvanted H1N1 Pandemic Influenza Vaccine”).

Health Canada approved the vaccine based on limited clinical testing, under the provision of an interim order. It is expected that additional safety data will be provided at a later date. The interim order that allows use of Arepanrix H1N1 is based on safety and immunogenicity data on an H5N1 vaccine prepared with AS03 adjuvant in adults and in children, and on 2 separate studies of an H1N1 vaccine prepared with AS03 adjuvant in adults. Canada Health assumes that Arepanrix H1N1 with adjuvant will behave similarly in children and adults as these two tested vaccines, and hence issued the interim order of approval. Let’s examine some of this information.

Adverse reactions: Two studies on H1N1 vaccine were conducted in adults 18-60 years of age. Adverse effects reported included inoculation site pain, redness, swelling, fatigue, headache, arthralgia, myalgia, shivering, and sweating. In general the reactions were reported more frequently in those receiving vaccine with adjuvant. For example, inoculation site pain was reported in 88.9% of 63 individuals who received vaccine with adjuvant, and in 59.1% of 66 who received vaccine without adjuvant. Similar observations were obtained in the second study with 124 individuals.

More extensive studies compared adverse effects of inoculating H5N1 vaccine plus adjuvant in 3,500 adults; the control group was inoculated with buffer. A similar range of symptoms was reported, the most common pain (73%) and muscle aches (33%). Incidence was less in those who received placebo (pain 12%; muscle aches 11.8%). In a separate study, ~300 children 3-5 and 6-9 years of age were given a full or half dose of H5N1 vaccine plus adjuvant. Pain, redness, swelling, fever, drowsiness, irritability, loss of appetite and shivering were more common in those who received the full dose of vaccine. No serious adverse effects caused by the vaccine were recorded.

Immunogenicity: In two separate studies in adults, the H1N1 vaccine lead to seroconversion of 97 and 98.4% of test subjects with or without adjuvant (conversion defined as an HI titer greater than or equal to 1:40). No immunogenicity studies of the H1N1 vaccine in children have been reported. There have been studies in children inoculated with an H5N1 vaccine, but I won’t consider those because the clinical experience is quite different from H1N1 vaccines. The full report can be found here.

Summary: In adults, the H1N1 vaccine approved in Canada induces protective immune responses. The immunogenicity of the H1N1 vaccine in children remains to be determined. In both adults and children, the use of adjuvant leads to more frequent adverse reactions but these are not serious. Consequently Canada Health recommends that children 3-9 years old should be given two half doses of vaccine three weeks apart, and children 10-17 years should receive the full dose (0.5 mL).

Canada has purchased 1.8 million doses of inactivated H1N1 vaccine without adjuvant, but those will not be available until November.


twiv-200Hosts: Vincent Racaniello and Jason Rodriguez

On episode #50 of the podcast “This Week in Virology”, Vincent and Jason review influenza 2009 H1N1 vaccine trials and protection against the virus conferred by the 1976 swine flu vaccine, then move on to a virus called XMRV and its possible role in prostate cancer.

Click the arrow above to play, or right-click to download TWiV #50 (54 MB .mp3, 74 minutes)

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Links for this episode:
One dose of influenza 2009 H1N1 vaccine without adjuvant is enough
Partially completed study on influenza 2009 H1N1 vaccine with MF59 adjuvant
1976 swine flu vaccine induces cross-reactive antibodies against influenza 2009 H1N1 strain
Explanation of hemagglutination-inhibition and microneutralization assays
FDA approves influenza 2009 H1N1 vaccine
XMRV is present in malignant prostatic epithelium and is associated with prostate cancer
Identification of a novel gammaretrovirus in prostate tumors
CDC page on Guillain-Barré syndrome

Weekly Science Picks
Jason Glass Microbiology
Vincent FluWeb Influenza Historical Resources Database

Send your virology questions and comments (email or mp3 file) to or leave voicemail at Skype: twivpodcast. You can also send articles that you would like us to discuss to delicious and tagging them with to:twivpodcast.

Adjuvant effect on H1N1 vaccine

There has been a great deal of discussion about the use of adjuvants to improve the immunogenicity of vaccines against the 2009 H1N1 pandemic influenza strain. What effect do these compounds have on the immune response?

Adjuvants are compounds added to vaccines that stimulate the immune response. They are often used when the antigen is in short supply, or does not induce a good antibody response. Because the 2009 H1N1 pandemic influenza strains do not replicate well in eggs, it has been suggested that adjuvants be used to ensure that there is sufficient supply of vaccine.

A recent study demonstrates very clearly the effect of adjuvants on the immune response. Mice were immunized with egg-produced 2009 H1N1 influenza vaccine with or without the adjuvant MF59. A boost inoculation was given on day 21. Sera were taken on days 13 and 21 and the antibody response was measured by hemagglutination-inhibition (HI) assay. If you don’t know how an HI assay works, please read my previous description. The results of the assay are shown in the figure.


One week after immunization with 0.5 micrograms of antigen, the average serum HI titer was 1:15 (bars labeled post1). This titer is barely higher than obtained when mice were immunized with buffer alone (PBS). The HI titer rose to 1:160 after the boost. When MF59 adjuvant was included, the first and second HI titers were significantly higher – 1:63 and 1:1280.

What do thes numbers mean? Protection of humans against seasonal influenza is generally believed to require a HI titer of 1:40 or more. Therefore when MF59 adjuvant is used in mice, one immunization is sufficient to confer protection against disease. Without adjuvant, two doses are required for protection.

Trials are ongoing in adults to determine the immunogenicity of 2009 H1N1 vaccines with and without adjuvant.

I know that many readers are concerned about the possible side effects of adjuvants. MF59 has been used for 12 years in seasonal influenza vaccines in Europe and is considered a safe adjuvant. However, the Centers for Disease Control and Prevention believes that the 2009 H1N1 vaccine will likely not be used with adjuvant.

Dormitzer, PR, Rappuoli, R, Casini, F, Wack, A et al (2009). Adjuvant is necessary for a robust immune response to a single dose of H1N1 pandemic flu vaccine in mice PLoS Currents: Influenza