Understanding the HPV vaccine’s risk

This needs more effort, but given the high burden of cervical cancer in India, waiting longer could be unethical

Published - February 05, 2018 12:15 am IST

hpv vaccination

hpv vaccination

The human papillomavirus (HPV) vaccine has run into more trouble. In January, a Rome-based epidemiologist, Tom Jefferson, of the Cochrane Collaboration highlighted in a paper worrying gaps in published data on the vaccine, designed to prevent HPV-related cervical cancer. Dr. Jefferson found that only two-thirds of the clinical trials on the HPV vaccine, manufactured by Merck Sharp and Dohme (MSD) and GlaxoSmithKline (GSK), had been published. This is particularly important in the light of his previous findings. Last year, Dr. Jefferson and other vaccine safety experts had questioned the European Medicines Agency’s (EMA) assertion that HPV vaccines are safe, after they found that the EMA had relied mainly on MSD’s and GSK’s analysis of clinical trial data to reach this conclusion. This is a problem because drug manufacturers have been known to cherry-pick data to show safety.

Clinical trials — experiments to gauge the effectiveness and safety of drugs — face a transparency crisis. As drug makers often don’t share all trial data, their claims cannot be re-examined by neutral outsiders. The flu drug Tamiflu, manufactured by Roche, is the most famous example of this crisis. In 2010, in the wake of the H1N1 influenza pandemic, the World Health Organisation (WHO) added Tamiflu to its core list of essential medicines. Following this, several countries spent billions of dollars on stockpiling the drug. But when a Cochrane Collaboration team led by Dr. Jefferson analysed again all the data on Tamiflu, some of which Roche had withheld earlier, they found that the drug wasn’t as effective as the company had claimed, and WHO dropped Tamiflu from its core drugs list in 2017.

Suspicions of illnesses

HPV vaccines have been in the middle of a controversy because of suspicions that they may be causing a trio of rare illnesses called Postural Orthostatic Tachycardia Syndrome (POTS), Complex Regional Pain Syndrome (CRPS) and Chronic Fatigue Syndrome (CFS). It is important to note that these are only suspicions; there is no evidence that these illnesses are caused by the vaccine. Such reports of a vaccine causing side effects — or safety signals — often emerge when new vaccines are launched, but more investigation is always needed to confirm these suspicions. It is also important to remember that even if HPV vaccines are eventually shown to cause these illnesses, researchers estimate that they probably do so in a small percentage of people. But regulators must still decide what to do with such safety signals. This is an especially critical issue for India, given that it is introducing HPV vaccines in its Universal Immunisation Programme (UIP). This means millions of girls in India aged between 9 and 14 years will get the vaccines for free.

Reports on POTS, CRPS and CFS in HPV vaccine recipients began emerging a few years after the vaccines were launched around 2007. POTS is an abnormal increase in heart rate when a patient stands up, while CRPS is unexplained, severe pain in a limb. CFS, as the name suggests, is debilitating tiredness that leaves patients unable to function normally. CFS is sometimes accompanied by POTS. All three are poorly understood conditions and often go undiagnosed. POTS and CFS sufferers may have other symptoms like nausea, sleep disturbances, and chronic pain, and unless a physician recognises this constellation of symptoms, she may confuse the illness for something else.

This difficulty in diagnosing these syndromes means that no one really knows their background incidence or how common these syndromes are in the general population. Some researchers estimate that upto 1% of adolescents have POTS, but others have questioned these estimates. This makes it tricky to establish if some people are getting these illnesses due to vaccines.

In 2015, after several doctors reported this cluster of illnesses in vaccine recipients from Denmark, Japan and Australia, the EMA reviewed these reports, along with trial data from MSD and GSK. It concluded that the rate of these illnesses in vaccine recipients wasn’t higher than background incidence, meaning that the vaccines were safe. But Dr. Jefferson and others questioned this conclusion. First, they said, it wasn’t clear how the manufacturers had identified POTS, CRPS and CFS cases in their data, given that different physicians use different diagnostic criteria. Second, the EMA couldn’t have compared the rates of the illness in vaccine recipients with background incidence, because the background incidence wasn’t known. Finally, the EMA had relied on MSD and GSK to analyse trial data, instead of analysing it independently. This was unacceptable, Dr. Jefferson said, because drug makers have a history of misrepresenting data to make their medicines look safe.

The HPV vaccine controversy is far from over. Dr. Jefferson is now in the middle of a systematic review of all trial data from MSD and GSK, which may or may not change what we know about HPV vaccines. The question then is, what should India do in the meantime? It’s a tough problem, says T. Jacob John, a Vellore-based virologist known for his work on polio vaccines. “There are no ‘yes’ or ‘no’ answers to such questions.” Decisions on vaccines often have to be taken using imperfect information, he says. India has the largest burden of cervical cancer in the world. Around 70,000 women die of it each year, and around 70% of these cases are caused by infections from HPV strains, which the vaccines prevent.

On the other hand, even if POTS and CRPS are shown to be caused by the vaccine, the incidence in vaccine recipients is likely to be very low. If it wasn’t low, it would have showed up in published data, despite the gaps pointed out by Dr. Jefferson, says Breann Butts, a paediatric resident at the Cincinnati Children’s Hospital Medical Centre in Ohio and a co-author of a 2017 review of HPV vaccine safety.

Risks and benefits

Given the rarity of these side effects and high burden of disease, waiting for more information on the POTS-HPV vaccine link could be unethical. And there are precedents of India going ahead with a vaccine, despite small risks. For example, the oral polio vaccine caused polio in one out of around every 1-2 million doses. But India accepted the risks of the vaccine because the disease itself was so rampant, says Dr. John. Eventually, from a burden of over 2 lakh cases a year, India became polio-free in 2014 using this vaccine.

In the case of the HPV vaccine too, India seems inclined to go ahead. K. Vijayraghavan, a member of India’s National Technical Advisory Group on Immunisation, which gave the vaccine the green signal last month, says there isn’t enough evidence on POTS or CRPS to delay the programme. There is a small risk of the vaccine being linked to the syndromes, but the benefits outweigh the risks, the Group has concluded. “The safest vaccine or drug is one that never gets used,” Dr. Vijayraghavan points out, because almost all drugs and vaccines have risks. Focusing on risks alone would mean that no vaccine would ever get approved.


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