Safety of 9-Valent HPV Vaccine Comparable to qvHPV

Pam Harrison

July 15, 2016

Overall, adverse event (AE) rates are comparable between the two vaccines, although injection-site AEs are more common with the 9-valent human papillomavirus vaccine (9vHPV) (Gardasil 9, Merck & Co, Inc) than with the quadrivalent HPV (qHPV) vaccine (Gardasil, Merck & Co, Inc), and they increase with subsequent doses for both vaccines, a new analysis concludes.

The analysis was published online July 15 in Pediatrics.

"The most common AEs (≥5%) experienced by 9vHPV vaccine recipients were injection-site AEs (pain, swelling, erythema)," note the authors, led by Edson Moreira Jr, MD, PhD, Brazilian Ministry of Health, Bahia.

"[But] discontinuations due to an AE and serious vaccine-related AEs were rare," they add.

The new analysis summarizes safety findings in seven phase 3 clinical trials of the 9vHPV vaccine involving more than 15,000 male and female patients aged 9 to 26 years.

In one of these studies (006), patients were randomly assigned to receive 9vHPV vaccine or saline placebo. In two further studies (001 and 009), patients were randomly allocated to receive 9vHPV or qHPV vaccines. In the remaining four studies (002, 003, 005, and 007), all participants received the 9vHPV vaccine.

The authors comment: "Because existing HPV vaccines prevent precancers due to HPV 16 and 18, the use of a placebo in subjects not previously vaccinated was deemed unethical."

"A 3-dose vaccination regimen given intramuscularly at day 1 and months 2 and 6 was evaluated in each study," the investigators write.

Almost 90% of recipients reported pain after receiving the 9vHPV vaccine, and 40% reported swelling. Slightly more than a third reported erythema.

The proportion of participants who reported pain, swelling, and erythema after receiving the qHPV vaccine was slightly lower, at approximately 83%, 29%, and 26%, respectively, over the entire three-dose series.

However, the differences in injection-site reactions were still statistically significant between the two vaccines (P < .001).

In contrast, the incidence of headache and pyrexia — the most common systemic AEs — were similar between the two vaccines.

In study 001, approximately 15% of 9vHPV recipients reported headache, and 5% reported pyrexia. In study 009, about 11% of 9vHPV recipients reported headache, and 5% again reported pyrexia.

By way of comparison, about 14% of qHPV recipients in 001 reported headache, and 4% reported pyrexia, whereas in 009, approximately 11% and 3% of qHPV recipients reported headache and pyrexia, respectively.

"The AE profile following 9vHPV vaccination was similar between genders [but] AE frequencies were generally lower in male than female subjects," Dr Moreira and colleagues state.

Seven study participants experienced serious vaccine-related AEs following receipt of the 9-valent vaccine, which was fewer than 0.1% of all vaccine recipients.

On the other hand, 2.3% of all vaccinees who received the 9-valent vaccine reported serious AEs, including 0.3% of recipients who reported a serious AE between day 1 and day 15 following receipt of any one of the three doses of the vaccine.

Serious reported AEs included elective and spontaneous abortions and appendicitis.

Twenty participants stopped receiving the 9vHPV vaccine because of an AE, and there were seven deaths, none of which were related to the vaccine, the researchers report.

There were also no reports of anaphylactic reactions due to the 9vHPV vaccine.

Further Analysis

AEs of particular interest were further analyzed. Syncope, for example, occurred in 36 9vHPV vaccine recipients out of more than 15,000 patients who received the 9vHPV vaccine; 20 of these cases occurred on the same day the recipients were vaccinated.

Two participants in study 001, one in each arm, developed the complex regional pain syndrome (CRPS). Dr Moreira and colleagues report that both CRPS cases were felt to be due to a previous injury.

Two additional 9vHPV recipients developed postural orthostatic tachycardiac syndrome (POTS), although this did not recur in one patient on receiving subsequent doses of the 9-valent vaccine.

The other patient was diagnosed with POTS more than 3 years after receiving the vaccine.

The incidence of new medical conditions, most commonly infection, was comparable between those who received the 9-valent vaccine and those who received the quadrivalent vaccine.

Investigators also assessed pregnancy outcomes among women with an estimated date of conception within 30 days before or after receiving any vaccine.

Among these pregnancies, 17.5% of 9vHV recipients experienced a spontaneous abortion. This compares with about 9% for qHPV vaccine recipients in study 001.

As the study authors point out, these rates are within the range normally reported for pregnant women who are not vaccinated with any HPV vaccine.

Rates of congenital abnormalities were also consistent with those in the literature.

"The 9vHPV vaccine was generally well tolerated in subjects aged 9 to 26 years," the researchers conclude.

"The demonstrated efficacy and favorable safety profile of the 9vHPV vaccine support widespread vaccination programs," they add.

The authors note that this combined analysis has several limitations. The overall safety database for 9vHPV vaccine is similar in size to that of the prelicensure database of qHPV vaccine; however, it is insufficiently sized to identify AEs occurring at a rate <1:5200. Such events are expected to be assessed in pharmacovigilance and postlicensure safety analyses, they note.

The study was funded by Merck & Co, Inc. The authors' complete financial disclosures are listed in the original article.

Pediatrics. Published online July 15, 2016. Abstract

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