Sunday, July 5, 2015

Public Health Gone Awry: Birth Dose of Hepatitis B Vaccine (IOM chimes in on lack of good vaccine data)

Hepatitis B is a serious disease.  It is highly prevalent in many countries in Asia (nearly 10% of Chinese carried the illness in 1992), but fortunately is of low prevalence in the US.  Per CDC, the overall reported US incidence rate for 2013 was 1.0 case per 100,000 population. After adjusting for under-ascertainment and under-reporting, an estimated 19,764 acute hepatitis B cases occurred in the US in 2013. 

Hepatitis B is due to a virus transmitted by sex, vertical transmission from mother to newborn, from blood products and iv drug abuse primarily. There is no casual transmission. The graphs below show that disease rates in all age groups were dropping even before hepatitis B vaccine was recommended for children with no risk factors, in late 1991.

Acute hepatitis B cases in children are now extraordinarily low: according to CDC, they have fallen "from 1.2 cases per 100,000 population in 1990 to 0.02 cases per 100,000 population in 2007," or one new, acute case per 5 million children per year.  (The same CDC report notes there were 87 perinatal cases reported from 22 states in 2007, a higher incidence. I am guessing that the perinatal cases were detected via maternal screening, while the prior estimate was derived from new clinical cases in older children.)

The reduction in disease incidence is fantastic. CDC's recommendation that all pregnant women be screened for hepatitis B in 1988, and that they and their newborns be treated, is likely the major reason for the decline in pediatric and young adult cases.

But CDC didn't stop there.  CDC made stepwise recommendations for hepatitis B vaccinations for all children (who were by age at lowest risk of hepatitis B) during the 1990s, and specified a dose at birth for all newborns in 2002, even though the risk to newborns with hepatitis B negative mothers was close to zero even then. (A well-publicized controversy in France over hepatitis B vaccine-induced multiple sclerosis in the mid 1990s had affected vaccination acceptance here.  The multiple sclerosis issue was never fully resolved, while the birth dose of hepatitis B vaccine may have contributed to greater vaccine uptake in the US, according to CDC.)

What do other countries with low prevalence of the disease do with respect to vaccinating newborns, a strategy that only helps those from Hepatitis B-infected families? Data on vaccine policy for all countries in Europe can be found on the ECDC website. 

Only 5 of europe's 31 countries recommend a dose of hepatitis B vaccine for newborns whose mothers are Hepatitis-B negative: Estonia, Lithuania, Poland, Portugal, and Romania.

Incidence* of acute hepatitis B, by age group and year --- United States, 1990--2007
Incidence* of acute hepatitis B, by age group and year --- United States, 1990--2007
* Per 100,000 population.

Incidence* of acute hepatitis B, by sex and year --- United States, 1990--2007
Incidence* of acute hepatitis B, by sex and year --- United States, 1990--2007
* Per 100,000 population.
 The bars indicate the rate per 100,000 (left y-axis) by sex; the line is the ratio (right y-axis) of the incidence rate among males compared with that among females.

But here's the thing:  

Public health decisions must balance risk and benefit to the entire population when determining policy.  In the case of vaccinations, it can be devilishly difficult to ascertain vaccine causality: the true rates, types and severity of adverse reactions remain questionable, since they may be delayed by weeks, months or even years following a vaccination. (Local reactions, rarely severe, such as redness, swelling, or tenderness at the injection site are easy to assign to a vaccine, while systemic reactions are not.)

When a disease is common in the population, in order to reduce its incidence via vaccinations, one can accept a certain degree of (estimated) adverse events due to vaccinations.  

When a disease is rare, but you are still vaccinating the same number of people, the number of  vaccine-induced adverse events does not drop--but your population benefit is reduced, since you are preventing fewer cases.  Given the reduced benefit, the adverse reactions may no longer be counterbalanced by the population benefit.  But have CDC's public health professionals reevaluated their hepatitis B vaccine policy in light of current disease rates? 

There is a big, big problem at the heart of vaccination policies: there simply are no reliable adverse reaction data.  In the specific case of hepatitis B vaccine, a newborn gets vaccinated on the first day of its life, and since the parents have no prior experience with that baby, it is especially difficult to identify a systemic adverse reaction to the initial dose of vaccine.

One "non-systematic" review reported:  "After reviewing the literature, we observed that complications seen after Hepatitis B vaccination are sudden infant death syndrome, multiple sclerosis, chronic fatigue syndrome, idiopathic thrombocytopenic purpura, vasculititis, optic neuritis, anaphylaxis, systemic lupus erythematosus, lichen planus and   neuro-muscular disorder."  Observed.  Not measured.  Who knows what it means?

The label for Glaxo's Engerix-B vaccine is vague regarding causality and severity of adverse events. A WHO information sheet on Hepatitis B adverse reactions is equally troubling, as the literature it cites is full of contradictions. Hand-waving by WHO to dismiss unwanted findings is unconvincing, when a vaccination policy appropriate for reducing hepatitis B transmission to newborns in low resource areas of the world (areas without assured screening during pregnancy) has been imposed in the US on our high resource, highly screened population of mothers and infants.

I know that what I am writing seems difficult to believe.  How could vaccines be licensed by FDA without good adverse event data?  But the fact is that when they are licensed, all the data FDA evaluates have been generated by the manufacturer.  Later, it is usually not beneficial to the manufacturer to actively seek evidence of harm.

The US government requests advice from the Institute of Medicine (founded in 1970 and part of the National Academy of Sciences, chartered by Congress in 1863) regarding issues of public health.

In 2012, an Institute of Medicine which had been asked to investigate the adverse event literature for Hepatitis B and other vaccines, issued this report

Adverse Effects of Vaccines: Evidence and Causality


Committee to Review Adverse Effects of Vaccines; Institute of Medicine; Stratton KFord ARusch EClayton EW, editors. Washington (DC): National Academies Press (US); 2012.
The report's conclusions state:
The committee acknowledges that some readers may have concerns about two aspects of the report. First, the committee does not make conclusions about how frequently vaccine adverse events occur. Secondly, the committee concluded, for most analyses, that the evidence is inadequate to accept or reject a causal relationship and some readers might interpret the committee's language in different and inaccurate ways. The committee offers concluding comments to address these two issues.
This report is not intended to answer the question “Are vaccines safe?”. The committee was not charged with answering that question. Other bodies make that determination and contribute to ongoing safety monitoring, including governmental agencies, care providers, and industry, as they determine the benefits and risks of marketing a product. At all levels, policy determining vaccine use requires a balancing of risks and benefits. As described in Chapter 1 and the Preface, that is outside the bounds of this committee's assignment. It should also be noted that where the committee has found evidence of a causal relationship, it does not make conclusions about the rate or incidence of these adverse effects.
Determining the rate of specific adverse events following immunization, in the general population or a subset thereof, is challenging. It would be possible, for example, to estimate a rate of the occurrence of a specific adverse effect in a vaccinated population or susceptible subgroup of interest. This could be done using a summary relative risk or absolute risk difference (e.g., estimated from a set of consistent reports reviewed by the committee) if there were large population-based studies of the occurrence of the adverse event in unvaccinated individuals (e.g., in the general population or susceptible subgroups of interest) who do not substantially differ from those vaccinated on any known, important confounders (e.g., age and exposure to other vaccinations or other agents or factors known to cause the adverse event). None of these preconditions is fully met for the adverse events reviewed in this report.
The committee also notes here that large epidemiologic studies that report no cases of the adverse event of interest in vaccinated study participants, if included in our analyses, raise particular concerns. If at least some cases of the adverse event occurred in a study's unvaccinated comparison population, an upper limit of the 95% confidence interval (CI) for the study's relative risk or absolute risk difference could be estimated, but one would be unable to rule out a possibly increased risk unless the vaccine was significantly protective against that particular adverse effect. Also, including such studies may have exacerbated problems with detection biases unless precautions were taken to ensure equal surveillance for the adverse event in the unvaccinated and vaccinated populations being compared...

So there it is.  In the absence of good data, it is hard to make good public health decisions--but they get made nonetheless, and the decision-making is population-based, independent of any individual's unique risk-benefit profile.

But for an individual, you can make an assessment that includes your risk factors for the disease, the vaccine efficacy (very good for Hepatitis B vaccine, although duration of protection is uncertain)
 and see how that balances with the (unknown) degree of risk from the vaccination.  If you are at more than infinitesimal risk for the disease, include a factor for the considerable health risks inherent in the disease, were you to develop it in the absence of vaccination. Caveat emptor.

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