Effect Measure

One of the good things about the pandemic flu threat (if you’ll let me put it that way) is the stimulus it has provided for vaccine technology. While current flu vaccines are still mired in horse and buggy technology of egg-based production, all sorts of alternative ways of making antigen or stimulating an immune response are being worked on. Most of them involve the major antigens of the flu virus, hemagglutinin (the H part of subtype designation) and neuriminidase (the N part). They are on the viral surface and easily “seen” by the immune system. There is also a little bit of another surface protein, called M2 that is visible on the surface. M2 is an ion-channel protein that is involved in the uncoating of the virus once it is engulfed by the cell. In the more acid environment of the little host cell derived vessel the virus uses to get into the cell, the hemagglutinin protein on its surface, which exists in two parts connected by a link, gets cleaved and allows the virus to emerge naked into the interior of the cell. The M2 protein is part of the apparatus that allows this to happen, and if you block its function with a drug, you get antiviral activity. The older class of antiviral drugs called adamantanes work this way. Unfortunately the virus readily becomes resistant to this drug class, but the M2 protein itself is pretty highly conserved in influenza A viruses, meaning that it doesn’t vary much. The other antigenic components (an antigen is anything that causes an immune response), the H’s and N’s, vary quite a bit, so every year or two we have to make new flu vaccines to take account that they now look different to the immune system. One strategy to avoid this is to try to make a “universal vaccine” that would work for all seasonal (and presumably pandemic) viruses without having to change them year after year. A vaccine against the relatively unchangeable part of the M2 protein that sticks outside the virus (M2e) is one of the prime candidates for this Holy Grail of the influenza vaccine world. Recently we have gotten press releases and some news stories that a company has made progress and has a “universal” vaccine that has passed an early test in people.

This sounds pretty good, but in the vaccine field there is more hype than hypodermics, so it’s always good to take a closer look. There is no scientific paper yet but there are enough details in the press release and a CIDRAP News story to get a first take on it:

A vaccine designed to offer protection against many strains of influenza viruses appeared safe in low doses and triggered a satisfactory immune response in a phase 1 clinical trial, the vaccine’s developer announced recently.

The vaccine, made by VaxInnate Inc., Cranbury, N.J., targets the M2 protein of influenza A viruses, a surface protein that differs little among different strains of type A. Existing flu vaccines target hemagglutinin (HA), a flu surface protein that often mutates, making it necessary to change the vaccine each year to cover the predominant strains in circulation. A vaccine targeting a protein found in all or most flu strains could reduce or eliminate the need to change the vaccine each year.

The company reported the results in an Oct 26 press release and at the Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America (ICAAC/IDSA) meeting, held Oct 24-28 in Washington, DC.

“VaxInnate’s M2e universal flu vaccine candidate has passed a critical initial test,” David Taylor, MD, the company’s chief medical officer, said in the news release. “We’re encouraged by these data, which demonstrate that the vaccine is safe and elicits potent immune responses at doses below a microgram [mcg] of vaccine antigen, and does so without the use of conventional adjuvants.” (Robert Roos, CIDRAP News)

The technology is interesting. They’ve linked the M2e antigen to a bacterial protein called flagellin that is recognized by a toll-like receptor (TLR5; more on TLRs here, here and here). Once TLR5 is bound by flagellin in a host immune cell it makes the cell produce a number of important cytokines (chemical alert messengers) which goose up the innate immune response.

So what was the “critical initial test”? Phase 1 clinical trials are very small scale studies meant to examine preliminary evidence for safety and efficacy. What does small scale mean? In this case it means a total of 60 patients divided into five groups, four getting two doses of varying levels of the vaccine, one getting two doses of placebo. 24 of the 60 normal healthy volunteers, all between the ages of 18 and 49 tolerated the two lowest doses well, according to the company’s press release, while those getting the two highest doses suffered “flu-like” reactions. The next question is whether the vaccine worked well enough at the two lowest doses to make it worthwhile to move forward with more comprehensive trials. This was evaluated by looking in the blood of the subjects for evidence of an immune response against the M2e protein. 75% had antibodies after one dose, and almost all (23 of 24) after two doses.

Now you can see the meaning of the phrase “critical first test.” If no dose could be found that didn’t produce an undesirable adverse reaction then that would be the end for this vaccine. But the two lowest doses were said to be well tolerated (we don’t know the details). And if there was no evidence that the vaccine produced an immune response, then the story would be over, as well. So it passed that test, too.

But there are a lot of unanswered questions. Let’s talk about the safety side first. Not finding significant adverse responses in 24 healthy and relatively young volunteers is not very informative. If you are giving a vaccine to tens or hundreds of millions of people, an adverse reaction doesn’t have to be extremely rare to be a big problem but still be missed by testing only 24 people. But that’s the nature of a phase 1 trial. Now the efficacy part. Here there is also a problem. The real test is whether the antibodies against M2e that are measured in terms of how much is being produced in the blood actually protects against infection. So a better test would have been a test to see if the antibodies were neutralizing antibodies, that is, able to prevent infection of the host cell. Even that isn’t the final answer, however. The real question is whether it prevents an intact organism (here we mean people) from getting sick after being exposed to a dose of the flu virus that would infect an unvaccinated animal. There is even a possibility that the vaccine could make it easier to be infected (there is something in dengue virus called antibody-enhanced infection).

The bottom line here is that it isn’t time to celebrate. If this idea works — and there is a reasonable chance it will — there is a lot to do before we’ll know.

A lot to do.

Comments

  1. #1 Albert
    November 16, 2008

    Hello revere, I noticed on your list of links on your blog that you have all of the flu forums and blogs, but not my site. Birflubreakingnews.com has also “never” posted one item from our site, ever. There is a network of sites that have obviously singled us out behind the scenes. Probably a bunch of gov’t sites, lol. You post Fla_Medic’s blog and Sophia Zoe’s, but not my site? Give me a break.

    AFT is the largest dedicated a/i site on the net, yet your group of a/i sites will never post our links. What am I missing here?

  2. #2 anon
    November 24, 2008

    you are banning members who post to other forums.
    Is it “allowed” to be member at AFT and post to effectmeasure ?

  3. #3 revere
    November 24, 2008

    anon: Who said I’m banning members of other Forums? I am doing no such thing. I have no idea who belongs to which forum and I added AFT to the blogroll last week. I only ban people who behave badly here and there are only a few people I’ve banned in 4 years.

  4. #4 anon
    November 25, 2008

    I meant Albert and was speculating that were the reason why AFT was “singled out”