The approval for use of the dengue vaccine is welcomed by clinicians as it is an additional measure to combat dengue, of which there have been more than 100,000 cases annually in the past three years.
Malaysia joined 14 other countries, including the Philippines, Indonesia, Singapore and Thailand in approving the use of this vaccine.
However, media statements have raised misperceptions which are not consistent with the scientific data.
This article seeks to correct them.
The National Institute of Health of the United States’ explanation of clinical trials is as follows (www.nlm.nih.gov/services/ctphases.html):
“Clinical trials are conducted in a series of steps, called phases – each phase is designed to answer a separate research question.
Phase I: Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
Phase II: The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety.
Phase III: The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
Phase IV: Studies are done after the drug or treatment has been marketed to gather information on the drug’s effects in various populations and any side effects associated with long-term use.”
A drug or treatment (in this instance, the dengue vaccine) is given approval for general use after Phase III studies have been found conclusive by regulators.
Since the vaccine is new, the objective of Phase IV studies is to obtain more information about its effects and any side effects with long-term use.
The media article stated: “The vaccine was approved for a post-registration (phase IV) clinical study for two years involving volunteers aged nine to 45. This means that only those who participate in the study will be able to obtain the vaccine, which will be made available in the next six months.”
The use of the word “volunteers” in the article gives the general impression that the vaccine is still experimental when it has been approved for general use.
Phase IV studies are carried on all recipients of new vaccines or medicines for the objectives stated above.
Licensing and National Immunisation Programme
A distinction has to be made between licensing and inclusion in the National Immunisation Programme (NIP), which is provided by the Health Ministry free of charge.
The history of vaccines in Malaysia is replete with examples of vaccines which have been approved for use years before they were included in the NIP: hepatitis B; measles, mumps, rubella; and human papilloma virus vaccines.
There are also vaccines which have been approved for use but are not in the NIP: influenza, pneumococcal, varicella and typhoid vaccines.
This is primarily because the Health Ministry considers the cost implications before including a vaccine in the NIP.
The dengue vaccine had been studied in the University Hospital in Kuala Lumpur and the General Hospitals in Ipoh, Seremban and Kuching. Of the 250 participants in the study, unsolicited adverse effects declined in frequency with each subsequent dose and were similar overall between the vaccine and non-vaccine (placebo) groups (53.8 vs 49.0%).
Serious adverse effects were reported by 5.5% in the vaccine group and 11.8% in the placebo group. No deaths were reported.
The authors concluded: “This study demonstrated a satisfactory safety profile and a balanced humoral response against all four DENV serotypes for CYD-TDV administered via a three dose regime in Malaysia.” [Source: Safety and immunogenicity of a tetravalent dengue vaccine in healthy children aged 2-11 years in Malaysia: A randomised placebo controlled Phase III study. Vaccine 31 (2013) 5814-5821]
The Asian dengue vaccine trial involved 10,275 participants aged two to 14 years, of which 6,710 in the vaccine group and 3,350 in the placebo group were analysed. 117 in the vaccine group and 133 in the placebo group developed dengue more than 28 days after the third injection.
Serious adverse events occurred in 402 in the vaccine group and 245 in the placebo group. 54 (1%) in the vaccine group and 33(1%) in the placebo group had serious events within 28 days of vaccination.
The “serious adverse effects were consistent with medical disorders in this age group and were mainly infections and injuries”. [Source: Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: A phase 3 randomised, observer masked, placebo controlled trial. Lancet. July 11, 2014. http://dx.doi.org/10.1016/50140-6736(14)61060-6].
In a pooled analysis of data from 33,266 participants worldwide in year three of the trial, hospitalization for dengue occurred in 65 of the 22,177 (29 in 10,000) in the vaccine group and 39 of the 11,089 (35 in 10,000) in the placebo group.
Hospitalization for severe dengue occurred in 18 of the 22,177 (81 in 100,000) in the vaccine group and six of the 11,089 (54 in 100,000) in the placebo group.
The authors concluded: “Although the unexplained higher incidence for dengue in year three among children younger than nine years of age needs to be carefully monitored during long-term follow-up, the risk among children two to 16 years of age was lower in the vaccine group than in the control group.” [Source: Efficacy and long term safety of a dengue vaccine in regions of endemic disease. New England Journal of Medicine. July 27, 2015. http://doi:10.1056/NEJMoa1506223]
The World Health Organization (WHO) stated in its position paper, “Vaccine efficacy varied by country ranging from 31% in Mexico to 79% in Malaysia.”
The efficacy against hospitalization from dengue was 72.7% for all ages and 80.8% in those more than nine years old. The efficacy against severe dengue was 79.1% for all ages and 93.2% in those more than nine years old. [Source: World Health Organization. Dengue vaccine – Position paper. Weekly epidemiological record No 30, 29 July 2016 page 357].
Balanced information needed
The media article quoted, “On the concerns the Ministry has, he said that earlier data had shown adverse effects of the vaccination for those who never had dengue before. Once they get the vaccination, they develop severe dengue. They can get dengue shock syndrome. It is possible.”
This statement focuses on earlier data on the two to five years’ age group, and is irrelevant as the vaccine is not approved or labelled for children under nine years of age.
As such, it is misleading, to say the least.
There is no perfect vaccine, just as there is no perfect medicine. There will always be adverse effects with any intervention.
The question is whether the benefits outweigh the risks.
The WHO has recommended that the vaccine be introduced in geographic settings where there is a high burden of disease.
It is very difficult to argue that the dengue burden in Malaysia is not high.
WHO has not recommended vaccine use in children under nine years of age, “consistent with current labelling” and “may consider vaccinating populations up to 45 years of age in routine programmes”. [Source: World Health Organisation. Dengue vaccine – Position paper. Weekly epidemiological record No 30, 29 July 2016 pages 362-363]
The Drug Control Authority’s approval mirror WHO’s recommendations.
Medical practitioners, policy makers and the media have a responsibility to provide accurate and balanced information to the public, which they are entitled to, so that they can make an informed choice.
Dr Milton Lum is a past President of the Federation of Private Medical Practitioners Associations, Malaysia and the Malaysian Medical Association. The views expressed do not represent that of any organisation the writer is associated with. The information provided is for educational and communication purposes only and it should not be construed as personal medical advice. Information published in this article is not intended to replace, supplant or augment a consultation with a health professional regarding the reader’s own medical care. The Star disclaims all responsibility for any losses, damage to property or personal injury suffered directly or indirectly from reliance on such information.