A little more than three weeks after vaccine producer Sanofi hinted at a safety signal with their Dengvaxia (tm) vaccine (see Philippines Halts Dengue Vaccine After Sanofi Issues Warning) - the crisis, and finger pointing, continues unabated.
This safety signal involves children who had never been infected with dengue, and received the vaccine. A number which has been estimated to be about 10% of the 700,000+ recipients in the Philippines.Recent studies suggest that dengue-naive children who received the vaccine are at an increased risk of seeing a `severe dengue infection' months or years later. And in recent weeks we've seen anecdotal reports from grieving parents of deaths, supposedly from severe dengue, among children who had been vaccinated.
Beyond the damage to public health, and the potential harm to recipients of the vaccine, this is rapidly turning into both a political and legal drama in the Philippines, with charges of corruption and negligence flying in all directions.
As discussed in detail a couple of weeks ago, there were warnings - published in major journals - suggesting just this sort of outcome was possible. One need look no further than a CIDRAP News report from July of 2016, which eerily presages this past month's events (see Contrary dengue vaccine response hints at possible problems with Zika).
A couple of weeks ago The World Health Organization promised `a full review of the data through the Global Advisory Committee on Vaccine Safety and SAGE, for revised guidance of the use of Dengvaxia®'.
Today (h/t Helen Branswell), the WHO updated their lengthy Updated Q&A on Dengvaxia, with new information on the investigation into Sanofi's dengue vaccine, along with interim recommendations that its use be curtailed pending a full report.
The short version is: ". . . . , until a full review has been conducted, WHO recommends vaccination only in individuals with a documented past dengue infection, either by a diagnostic test or by a documented medical history of past dengue illness."Given the difficulties of positively establishing whether a child has had dengue - at least in the context of a mass vaccination program - this will likely discourage mass vaccination in that age group, at least until a final decision is rendered.
What follows are just a few excerpts from a much, much longer document. Follow the link to read it in its entirety.
Updated Questions and Answers related to the dengue vaccine Dengvaxia® and its use
Published 22 December 2017
This document takes into account new and unpublished data that were communicated by Sanofi Pasteur to WHO in November-December 2017.
WHO published the recommendations of the Strategic Advisory Group of Experts on Immunization (SAGE) on the use of Dengvaxia® on 27 May 2016 (1), and subsequently a WHO position paper on dengue vaccine on 29 July 2016 (2).
Following the disclosure to WHO of new data on Dengvaxia® by its manufacturer, Sanofi Pasteur, as described in more detail below, WHO has initiated a process engaging independent external experts to review the data in detail. This process is expected to lead to revised recommendations from SAGE in April 2018, and to an updated WHO position paper on dengue vaccine thereafter.
The purpose of this document, prepared by the WHO Secretariat, is to supplement the WHO position paper on Dengvaxia® of July 2016 until WHO has issued an updated position paper on dengue vaccine, based on advice by SAGE. WHO Secretariat recommends that the July 2016 position paper be read in conjunction with this document.
This document replaces a questions and answers document web-posted by WHO on 30 November 2017.
What was WHO’s position on the use of Dengvaxia® as published in July 2016?
The decision of whether to introduce a new vaccine in a country is a decision of governments, not of WHO. However, WHO provides recommendations in the form of position papers to help country decision-making. These recommendations are based on the advice of SAGE (7), WHO’s principal independent expert advisory committee on vaccination. Based on their advice and the data available as of April, 2016, a position paper on the dengue vaccine was published in July 2016 (8). This position paper presents a conditional recommendation on the use of the vaccine for areas in which dengue is highly endemic as defined by seroprevalence in the population targeted for vaccination. Seroprevalence refers to the proportion of people in a population who have already been infected with a dengue virus, i.e. the proportion of seropositive individuals. Based on the difference in performance of Dengvaxia® in seropositive and seronegative individuals, seroprevalence thresholds were considered the best approach to define target populations for vaccination. Trial results and mathematical modeling suggested optimal benefits of vaccination if seroprevalence in the age group targeted for vaccination was in the range of ≥70%. WHO developed guidelines on how to determine the seroprevalence in an area to help countries that were considering use of the vaccine (9).
Although at the time of the policy formulation no evidence of an increased risk of severe dengue in seronegative individuals aged 9 years and above was apparent from the limited available data, the possibility of low efficacy and an elevated risk of severe dengue in vaccinated seronegative individuals was mentioned in WHO’s position paper because of the observations in the younger age group. This possibility was considered in the mathematical models used to inform the WHO position. SAGE considered further research into the efficacy and safety of the vaccine in seronegative persons a high priority (8) (10) (11). Hence, WHO requested that Sanofi Pasteur provides more data on efficacy and safety in seronegative vaccine recipients.(SNIP)
How can one explain the excess cases of severe dengue in the vaccinated seronegative population?
The reasons for the excess cases are not fully understood, but a plausible hypothesis is that the vaccine may initiate a first immune response to dengue in seronegative persons (e.g. persons without a prior dengue infection) that predisposes them to a higher risk of severe disease. That is, the vaccine acts as a “primary-like” infection and a subsequent infection with the first wild type dengue virus is then a “secondary-like” clinically more severe infection. This hypothesis is illustrated in the Figure below. However, other hypotheses are possible and, at this stage, there is no definitive explanation. Of note, it is not the vaccine itself that causes excess cases, but rather that the vaccine induces an immune status that increases the risk that subsequent infections are more pronounced.
What is WHO interim position towards the use of Dengvaxia®?
WHO has initiated a process engaging independent external experts to review the new data generated by Sanofi Pasteur in order to provide advice on revisions to the WHO policy position paper from 2016. On 6-7 December 2017, the WHO Global Advisory Committee on Vaccine Safety (GACVS) reviewed the data and subsequently published a statement related to the safety of the product (16).
WHO acknowledges that in high seroprevalence settings, the vaccine can have significant population-level benefits. However, until a full review has been conducted, WHO recommends vaccination only in individuals with a documented past dengue infection, either by a diagnostic test or by a documented medical history of past dengue illness.
Any further guidance, including a review by SAGE and update of the WHO position paper on Dengvaxia®, will likely be available no earlier than April 2018 after a rigorous review of the new data and additional activities, such as population based modelling, are undertaken. Meanwhile, WHO encourages the development of a rapid diagnostic assay to determine past dengue infection.
Regardless of the actual risk of injury from this vaccine (which remains a matter of some debate), Dengvaxia's reputation - and the public's perception of the safety of other vaccines - has taken a significant hit.
Which in the end, could turn out to be the biggest loss of all.