Saturday, March 20, 2010

Prevnar and such as

Let’s look critically at what is known about Prevnar starting with the 2 prelicensure trials. Here is the main one
Look at the study design first of all. What are they measuring and does it make sense clinically? The primary outcome is IPD caused by the serotypes in the vaccine. Secondary outcomes include all cause IPD, but wouldn’t it more relevant to include all invasive bacterial diseases? Would it be a success if we replaced IPD with other pneumonias, ear infections, bacteremia etc? Notice how after 3 years and 17 cases of IPD the randomization period was stopped by design and then less than a year later there were 56 cases to review.
There are other concerns with the study design. Since pneumococcus is normal flora in children, addressing long term effects of altering the normal flora is critical. Again, are there other bacteria replacing the infections prevented from these few serotypes of pneumococcus? What about the remaining 80 something serotypes of pneumococcus? Are we getting more or less virulent bacteria in the normal flora because of prevnar? What about the antibiotic resistance of these replacement serotypes? The initial 2 studies didn’t look at this but post after mass vaccination, we do have some studies looking into what happened.
Initially we have this:
(from 403.2 per 100,000 in 1995-2000 to 134.3 per 100,000 per year in 2001-2003, P<.001)

Then after the initial dramatic decrease in IPD, the replacement serotypes fill the partial void:
"However, between 2001-2003 and 2004-2006, there was an 82% increase in invasive disease in Alaska Native children younger than 2 years to 244.6/100,000 (P = .02). Since 2004, the invasive pneumococcal disease rate caused by nonvaccine serotypes has increased 140% compared with the prevaccine period (from 95.1 per 100,000 in 1995-2000 to 228.6 in 2004-2006, P = .001)"
What other bacteria are replacing the vaccine specific serotypes?
JAMA 2004 Aug 11;292(6):716-20
"CONCLUSIONS: Streptococcus pneumoniae carriage, specifically of vaccine-type strains, is negatively associated with S aureus carriage in children. The implications of these findings in the pneumococcal vaccine era require further investigation"
Lancet 2004 Jun 5;363(9424):1871-2
"These findings suggest a natural competition between colonisation with vaccine-type pneumococci and S aureus, which might explain the increase in S aureus-related otitis media after vaccination."
Anyone in clinical practice recall an explosion of MRSA in children since 2000? It's no fun holding down a 3 month old to drain an abscess.
There seems to be an accepted causal relationship between prevnar's eradication of its 7 serotypes and the emergence of serotype 19A as the dominant pathogen of IPD. Serotype 19A which is responsible for multidrug resistant IPD. Meaning children requiring quinolones to clear their ear infections.
The fact is, we don't know what effects Prevnar 13 will have any more than we knew what Prevnar 7 would do. If you want to look at the studies of clinical efficacy on Prevnar 13, we can; but it's rather disturbing seeing how the bulk of the research was done outside of the US and often on those living in extreme poverty. The new vaccine has been tested on populations which aren't intended to get the vaccine after licensure.
The mechanism for pneumococcus evading the antibodies from prevnar 7 , capsid switching, is a well accepted characteristic of the bacteria. Prevnar 13 will simply add another 6 antibodies and we have no reason to believe that this slightly enhanced selective pressure will give us anything other than a more robust version of 19A.
Prevnar has been the most lucrative pharmaceutical for Wyeth some of the years between 2000 and now. What benefit did we receive? Prevnar wasn't able to get an indication for preventing meningitis (bacterial meningitis in infants practically vanished in the years prior to prevnar's release). Maybe prevnar decreases IPD including pneumonia in older children and adults, but again all cause pneumonia and invasive bacterial infections would be a proper comparison AND the mothers who consented to have their infants vaccinated with prevnar weren't consenting to protect older children and adults.
Any benefit on ear infections would have to be looked at in the context of all cause ear infections and longitudinal serotype replacement phenomenon. Also the ear infection outcome has to be looked at in the context of more recent recommendations to allow the majority of clinical otitis presentations to resolve without antibiotic therapy.
Look at how they compared prevnar 13 to prevnar 7 in the US trials and only looked at immunology not any clinical outcome.
Pretend Prevnar is a pill for a minute, a pill like Zetia. If it were a pill to be given to 2 month olds and the long term impact were uncertain would you recommend it to every 2 month old in the nation and "hey we'll figure out what went right and what went wrong a decade later"…..
Any preventive test or intervention is capable of doing more harm than good. We must be extremely careful mucking with the normal flora of children. The bright minds reading the articles on this site are capable of critical thinking. Now ask yourselves who has more to gain financially by manipulating people, the makers of homeopathic snake oil or Wyeth.
"Prevnar sales surged 24% in 2007 to $2.4 billion, making it the first vaccine to exceed $2 billion in annual sales."