Antibody responses as determinants of efficacy in influenza vaccine studies by Truman Green

In an October 24, 2009 post to the online site, The Daily Galaxy, Rebecca Sato quotes Mike Adams, editor of Natural News.com, who claimed: “There has never been a randomized-double-blind, placebo-controlled trial on the efficacy of the flu shot. (A fact that not even most doctors know).” After the article commenters hotly debated the credibility of Adams’ claim, and one even threatened to cancel the Galaxy link to his own site if Sato’s article was not removed.

As evidence that both Sato and Adams are guilty of “anti-science lunacy,” this commenter (Jojo) offered a link to the site, Science Based Medicine and the article, Flu-Vaccine Efficacy. In this article by Mark Crislip, the vaccine efficacy studies are broadly discussed. Crislip’s conclusion is that the clinical vaccine efficacy testing has been done under the most rigorous scientific scrutiny and the results can be confidently relied upon.  He writes: “I find these types of studies compelling. They also make me optimistic for the H1N1 vaccine in that the match between the virus and the vaccine is excellent and we should get high levels of protection from the vaccine in those that can mount an antibody response.”

Crislip’s referral to “antibody responses” and “match between the virus and the vaccine” indicate that he has an excellent grasp of the procedures  used by the vaccine industry to gauge the efficacy of their products, as well as the problems inherent in attempts to match the vaccine with the antigens present in seasonal or so-called pandemic viruses.

It is probably little known that, with the exception of some recent cell-mediated immunity experimentation,  the vaccine industry’s entire efficacy-testing protocols are developed around the supposedly self-evident truth that those “antibody responses” referred to by Crislip, yield reliable information about whether a vaccinated person has acquired protection from a future natural influenza virus infection or not. Simply stated, vaccine researchers judge vaccine efficacy simply by counting the number of antibodies present in a titer of the subject’s serum after inoculation with a dead or attenuated live antigen of the virus from which future protection is sought–usually the genetically-correlated surface glycoprotein, hemagglutinin.

But the question remains: Is the presence or absence of antibodies a reliable  measure of future protection, or are these “antibody responses” in fact, merely convenient and self-serving surrogate markers for protection invented by the vaccine industry as tools by which they can  claim that they know how much protection their vaccines offer against future influenza infection?

Surprisingly, statistical information about the prevalence of antibody responses in vaccinated trial subjects is the endgame. The vaccine industry’s claim is: “If you have an antibody response to our vaccine, you will very likely not get the flu.” And their assessment of immunogenicity is reached wholly by employing a direct ratio algorithm to assess the relationship between the number of antibodies and the amount of protection obtained. Ongoing investigations to determine whether those with immune responses to the vaccine  in real life–over the course of a flu season–acquire clinical case symptomology amounting to a bout of the flu have never been done.

Similarly, although the industry often refers to their trials as being “randomized, double-blind and placebo-based,” these standards refer only to a determination of which subjects acquire antibody responses, not which subjects get the flu. Legitimately-controlled studies regarding clinical diagnoses of influenza would necessarily entail the division of a chosen cohort into two groups–one to receive the vaccine and the other to receive a placebo.

Such trials have never been done, and in this regard Mike Adams and Rebecca Sato are correct.

The pharmaceutical industry claims that placebo-controlled clinical trials for vaccines would be unethical because they would endanger the health and welfare of the group which would be given the placebo and not the vaccine. Their reasoning is that the efficacy of vaccines in preventing disease is already a well-proven fact, and that to withhold vaccines from the placebo group would be tantamount to subjecting them to the very infection which the vaccine was invented to prevent, all of which implies that it is the vaccine industry’s concern for the welfare of their test subjects, rather than their reticence in legitimately testing an already-licensed product, which inspires their refusal to do valid placebo testing.

Medical journalists, Shannon Brownlee and Joanne Lenzer, writing for the Atlantic, recount the placebo prohibition in their conversations with several CDC and NIH officials. Lone Simonen claims that: “It is considered unethical to do trials in populations that are recommended to have vaccine.” The authors conclude: “…this is a stance that is shared by everybody from the CDC’s Nancy Cox to Anthony Fauci at the NIH.”

From the article: “In a phone interview, Fauci at first voiced the opinion that a placebo trial in the elderly might be acceptable, but he called back later to retract his statement, saying that such a trial ‘would be unethical.’”

Also noted in the Atlantic article, Tom Jefferson of the Cochrane Collaboration, calls for placebo-based trials of all influenza vaccines and believes: “We have built huge population-based policies on the flimsiest of scientific evidence. The most unethical thing to do is to carry on business as usual.”

Are such claims that placebo-controlled vaccine trials would be “unethical” justified, or are they rationalizations by the vaccine industry which would rather not subject its fantastically profitable products to the kind of scrutiny which might disprove their usefulness, and perhaps even render the vaccine industry liable for massive wastage of public funds and the suffering of unnecesssary side effects by millions of people?

Vaccines are the motherlode of pharmaceutical manufacturing and marketing because their sales are subject to governmental programs in disease prevention, including many instances in which they will become mandatory for employees in the health industries and armed forces, and are often required for school children as a condition of public school admittance. Directives  by various national and provincial health departments that certain vaccines against seasonal or pandemic viruses are necesssary to prevent dangerous–even fatal–infections, are, in effect, gratuitous sales marketing and advertising campaigns for the vaccine industry.

In addition to the unproven  reliability of using antibody responses as predictors of future infection, there is another “gorilla-in-the-room” type of conundrum: People who will  be, in theory, most capable of producing antibody responses will also be those who will  least require a boost in their immune capability. Healthy people, with well-functioning immune systems rarely, if ever, get the flu. Conversely, those whose immune systems are compromised by other chronic or acute medical conditions, genetics or unhealthy living environments, will be those who are least likely to respond positively to an inoculation of foreign molecules comprised of dead or attenuated live pathogens simply because their immune systems are least capable of effectively manufacturing and deploying protective substances, whether specific immunoglobulins alone, (antibodies), or any of the vast array of molecules of an extremely complex immune system.

Randomized, double-blind placebo-controlled clinical studies are the gold standard for assessing the efficacy and safety of all drugs. The trials must be randomized so that an unbiased cohort or group of subjects will not be chosen–perhaps a group in which the “healthy user effect” will invalidate the results, or a group the members of which are more likely than average to have pre-existing or clinical cases diagnoses of the symptoms in question, such as might occur in hospitals or in those who are injection drug users. The “double-blind’ aspect refers to the stipulation that neither subject nor the administering physician or medical techno will know which subject has been given the placebo and which has been given the medication or vaccine; the “placebo” requirement is that one group will be given a harmless and benign medication and the other group will receive the medicine or vaccine which is to be assessed.

The human immune system, briefly

In addition to producing antibodies used by the vaccine industry to gauge efficacy, the human immune system is a failsafe complexity of systems, organs, proteins and molecules, each specifically designed to do a complementary job of protecting the human organism from foreign biological aggression. From the first line of defense, the skin, and the particle-blocking hairs in the nose and ears, to the various kinds of white blood–cells-lymphocytes, t-cells, neutrophils, basophils and phagocytes–to the cytokine interferons which interfere with viral replication,  to the protective actions of hormones and the interleukin signalling systems, including perhaps any system or organ such as the liver and kidneys which have filtering capabilities, the overall health of the immune system, as well as the subject in general, determines which person will contract a bout of influenza and which person will not. Antibody responses are certainly  part of this complexity, but their use as validly-conceived surrogate markers for protection, has not been verified  by the kind of clinical studies– including clinical case diagnostic follow-ups –that would be required to justify the claims of the vaccine manufacturers.

GSK explains

GlaxoSmithKline, one of the world’s   foremost vaccine manufacturers, provides an enlightening overview of  its products in the review, “A vaccine manufacturer’s approach to address medical needs related to seasonal and pandemic influenza viruses.”  This review presents  not only specific information about GSK’s vaccines, FluLaval and Fluarix, but also an account of W.H.O.’s  criteria for deciding which vaccines it will recommend to national governments, as well as the clinical trial methodology used in assessing the efficacy and safety of its vaccines.

From the GSK review: “The main immunogenic factors are the virus surface glycoproteins hemagluttinin (HA) and neuraminidase (NA). There are several antigenic forms of HA and NA for influenza A which are classified into different subtypes based on various combinations of these antigens.”

Following  is an example of GSK researchers’ immunogenicity determining  methodology:

“Geometric mean titres (GMT) of serum antibodies peaked 21 days after vaccination and remained above the protection level (i.e.% of vaccines above an HI (hemagluttinin inhibition) of 1:40) for all three strains for up to 12 months in both the adult and elderly populations. In a study conducted in elderly institutionalized patients, GMTs were also shown to be higher 6 months after vaccination with Flurarix than before vaccination. These observations suggest that the vaccine will provide protection for the whole influenza season in a high percentage of both adult and elderly persobns.”

All of which can be translated as: “We have counted the number of antibodies in subjects’ blood and it is shown to be at least fourfold from baseline, so we interpret this to mean that the vaccine will protect from future natural  infection with the the virus against which proteciton is sought.” It is to the credit of the GSK writers that they have used the word, “suggest,” and to the detriment  of the vaccine industry that it offers such suggestions to the world as proof that the elicited antibody responses furnish protection from naturally-occuring infection entirely without proof that such is the case.

As mentioned early in this paper, this is the endgame–whether the number of antibodies exceeds the industry-developed ummunogenicity requirements. There are no further attempts in any of the studies or reviews I have investigated to determine whether the presence of antibodies in serum titers equals influenza virus immunity in real life.

GSK’s writers proclaim: “These observations suggest that the vaccine will provide protection for the whole influenza season.” But are these claims of efficacy in line with established antibody paradigms in the diagnoses of other diseases?

 Regarding tuberculosis, it is well-known that among those who are shown to be positive for TB antibodies, it is not known which will contract an active case of TB until more testing and follow-up procedures are completed.

In HIV/AIDS theory, the presence of antibodies to the so-called “Aids Virus” is almost universally believed to mean that the subject will ultimately contract a catastrophic immune system  failure–not immunity has been acquired.

Similarly, having antibodies to any of the hepatitis viruses is not indicative that hepatitis will or will not occur, only that the subject has, at some time in the past, come into contact with the hepatitis antigens.

While the aforementioned Mark Crislip may “…find these kinds of studies compelling,” I find that, while they may be interesting preliminary indications  that the immune system is aware of the presence of antigens,  the determination of whether this knowledge will result in protection from a clinical case diagnosis of influenza can only be acquired with legitimate randomized, double-blind, placebo-controlled efficacy trials.

Time to demand  legitimate testing of flu vaccines

The current World Health Organization-proclaimed 2009 A(H1N1) “pandemic” has raised much controversy and suspicion in at least fifty percent of the American and Canadian populations. In addition to the ubiquitous “pandemic denial” held by many (including this writer), it is now time that we demand that all influenza vaccines must be tested using the same gold standard of efficacy required of all other drugs.

Truman Green