Friday, October 9, 2009

Why Am I Concerned about Safety of Swine Flu Vaccines?

My friend Mark Crispin Miller has urged me to be more specific about why I am concerned about the safety of swine flu vaccines in the US. In a nutshell:

1. Newness

I am always concerned about new drugs and vaccines. A former FDA Commissioner, Dr. Jane Henney, once said she did not use drugs during the first year they were on the market, and advised others to likewise avoid them. The reason is that many drugs and vaccines have caused serious side effects that were not picked up, or not considered enough of a concern, during initial clinical trials. Rotashield vaccine is a good example: intussusception (causing bowel obstruction) did occur but was overlooked in prelicensure trials because it was judged unrelated to the vaccine, and a million babies received the vaccine before it was taken off the market in 1999. Rotashield caused 22 times the expected rate of intussusception in infants, causing much more harm than good... but was marketed for 11 months. Because this was the first time intussusception was ever connected to a vaccine, it wasn't considered plausible that a vaccine could cause this until after 1,000,000 children were exposed.

Pre-licensure trials typically involve only one to several thousand subjects for short periods of time.

2. The currently available evidence is thin and inadequately collected

There are few published studies of swine flu vaccine. The Greenberg et al. study from Australia (Response after one dose of a monovalent influenza A H1N1 2009 vaccine--preliminary report; NEJM 2009; epub Sept. 10) is a relatively high quality study. How was vaccine safety evaluated? By using a diary card for 7 days post-vaccination. The 240 subjects returned on day 21 for a blood draw, and presumably some data were collected then, but it is not clear from the published report what safety information was obtained after 7 days. Local symptoms like a sore arm were reported by 46% of subjects, and systemic symptoms such as headache, muscle aches or malaise were reported by 45%. Subjects were healthy adults aged 18-64.

The authors stated, "No deaths, serious adverse events or adverse events of special interest were reported." The investigators did specifically query subjects about several neurologic and immunologic events, including Guillain Barre Syndrome. However, it is unclear how actively other adverse events were sought, if at all, after the initial seven days post-vaccination.

The authors acknowledge that, "The full safety profile of the H1N1 vaccine has not yet been elucidated. Population-based postlicensure surveillance will be required for all H1N1 vaccines, especially to assess rare outcomes, such as the Guillain-Barre Syndrome." And they point out that they studied a population of healthy adults, and "trials need to be conducted in other populations that may have different responses to the vaccine, such as the elderly, children, and those with impaired immunity."

What further concerns me are the later side effects that will not be collected, or not attributed to the vaccine due to lack of "biological plausibility." Since there do not exist reliable scientific criteria for assigning causality to vaccine adverse events, those the vaccine causes are likely to be dismissed as coincidental. Compounding this problem, the brief periods of active surveillance are insufficient to identify later reactions. When it takes 10-14 days to achieve peak antibody levels, a week of active surveillance for side effects is clearly inadequate.

3. The Liability Waiver... blanket immunity in the absence of willful misconduct

As I've noted previously, swine flu vaccine manufacturers can only be sued for damages if they are guilty of willful misconduct. As long as they don't know about safety problems, they cannot be held liable for them. This thoughtless language in the Public Readiness and Emergency Preparedness Act, which regulates pandemic vaccines, may induce manufacturers to perform minimal safety testing in order to avoid potential liability. Don't you think corporate attorneys have so advised their clients?

4. When the program isn't transparent, the result is lack of trust.

I expect the government, which is supplying free swine flu vaccines, to advise recipients honestly about them. Live flu vaccines have very low efficacy in adults, compared to injected subunit vaccines. How attractive would a nasal vaccine that was only 29% effective at preventing influenza be to you, when the injected vaccine had 72% efficacy? Yet this is what Monto et al. recently reported in the NEJM about last year's seasonal vaccine. It makes you wonder why live flu vaccines are even licensed for adults. And how good are they in children? Better--but the data are limited.

Some hospitals are refusing live nasal vaccines for employees. That is wise: they are concerned the live viruses could be transmitted to patients, especially those with impaired immunity. They should also be concerned about efficacy (29% isn't very good) of live nasal vaccine. Why didn't government tell the public about these concerns? Why didn’t government tell the public it issued a liability waiver to the manufacturers?

Schools offering these vaccines don't seem to be aware of potential problems such as vaccine virus transmission to immune-compromised students.

5. Benefit and risk should be compared

Yes, there are serious swine flu illnesses and deaths in a young, healthy population. But how frequent are they? How good is the vaccine at protecting against them? The very best flu vaccines are about 70% protective against catching the disease, which is the measure you are interested in. Most studies measure the rise in antibody levels, which may not reflect actual protection.

During 4 weeks in September there were 182 confirmed influenza deaths in the US. Though not a small number, it is not a big number either compared to seasonal flu. Admittedly incomplete, WHO has reports of just 4100 deaths worldwide since the pandemic began. There have been 60 deaths in US children related to swine flu since the pandemic began.

Cities (like Boston and New York) that had a lot of swine flu cases in the spring are having few now, suggesting a large enough number of people (perhaps 50% or more to induce this effect) had subclinical infections, generating herd immunity. It is likely many will be vaccinated who are already immune. In the Australian trial 31.7% of vaccine recipients had antibodies against swine flu before they were vaccinated, even though they had no symptoms of disease. The effect of preexisting antibody spuriously raises vaccine efficacy statistics in some trials, and reduces the need for vaccine.

If you have a neuromuscular disorder or lung disorder, you are at higher risk of a serious outcome from flu. Thus your benefit from vaccination is greater.

Vaccination was once intended for only the most serious illnesses. Doctors knew some children would develop encephalopathies (brain injuries) as a result of vaccination, but the risk was worth the benefit. Over time, and as the profits from vaccines have risen, "mission-creep" has led to increasing numbers of vaccines for less serious illness, even moving vaccine development into areas of non-infectious diseases like cancer. During this process, appreciation of vaccine risks got marginalized.

The benefit of vaccination should be balanced against the risk, but as yet we don't know the risk. I do my best to balance the known and potential risks and benefits as I advise people regarding vaccination, and I hope readers of this blog do also. Vaccination shouldn't be a “one size fits all” intervention.

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