Journal of Infectious Diseases Advance Access published August 5, 2016

Journal of Infectious Diseases Advance Access published August 5, 2016 1 Critique of WHO Approval of a Dengue Vaccine Scott Halstead cr ipt Corres...
Author: Allan Morrison
3 downloads 2 Views 813KB Size
Journal of Infectious Diseases Advance Access published August 5, 2016

1

Critique of WHO Approval of a Dengue Vaccine Scott Halstead

cr ipt

Corresponding Author: Scott Halstead, MD, [email protected]

In mid-April 2016, the World Health Organization’s (WHO) Scientific Advisory Group of Experts on Immunization (SAGE) recommended that dengue-endemic countries consider using

us

Sanofipasteur’s chimeric yellow fever dengue vaccine (Dengvaxia) to immunize populations with high levels of dengue endemicity, ages 9 – 45 years-old.[1] Dengvaxia was made by

an

splicing yellow fever 17D viral genes with those of the four dengue viruses (DENV) and it is administered in three doses over a period of one year.[2] WHO’s Dengue Vaccine Working

M

Group developed recommendations to SAGE based upon published year 1 – 3 data from Phase III clinical trials involving more than 35,000 children, ages 2 – 16 years, in 10 dengue endemic

pt ed

countries. [3-6] These data were supplemented with unpublished data supplied by the manufacturer covering up to six years post-vaccination. [7] During the first two years after immunization, compared with placebo controls, Dengvaxia reduced dengue disease prevalence, mild and severe, by 57% with a lower efficacy against illnesses caused by DENV-1 and -2 compared with DENV-3 and -4. [3-5] However,

ce

during the third year after vaccination the protective efficacy dropped to 16.7% (Vaccinated 65/22,177 vs Placebo 39/11,089). [6] An analysis of year 3 breakthrough DENV disease found

Ac

the vaccine to be asymmetrically protective and enhancing.[8] In Asian sites, the dengue hospitalization rate was significantly higher among vaccinated children, age 5 years or younger,

20/2029 (0.99%), than among controls, 2/1005 (0.2%), a relative risk of 4.95, p = 0.03.[8]

© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail [email protected].

2 Concerning hospitalizations in seronegative children 9 years and older, SAGE wrote; “There are few data to support or refute any risk in seronegatives greater than 9 years of age…. In CYD14

cr ipt

and CYD15, over 70% of the population in this age group was seropositive, and this increased

with age up to 16 years. The relative risks were below 1 over time in this age group (consisting of both seropositives and seronegatives). [7] Because only 8% – 19% of children enrolled in

clinical trials were bled prior to receiving vaccine, complete data based on the serological status

us

at the time of vaccination of all 65 hospitalized children is not available.

In late 2015 and early 2016, Dengvaxia was licensed by the governments of Brazil, Costa

an

Rica, El Salvador, Mexico Paraguay and the Philippines, where 1 million doses were purchased for nationwide vaccination of 9 year-olds.[9-11] Although SAGE concluded that Dengvaxia can

M

be safely administered to seronegative individuals 9 years and older, several lines of evidence suggest that Dengvaxia, when given to seronegatives of any age permitted breakthrough DENV hospitalizations during year 3:

pt ed

1. Vaccination of seronegatives raises enhancing antibodies. Seronegative children comprised a substantial portion of total vaccinated, the median dengue seronegative prevalence varied from 54.2% among 2 – 5 year-olds to 21.5%

among 9 – 16 year-olds.[12] These seronegative children responded to one or

ce

more doses of Dengvaxia by regularly developing DENV 1 – 4 neutralizing antibodies although these children were poorly protected against dengue disease.

Ac

[3-5] A similar protection outcome was observed in sera from 23 Singaporean

adults bled five years after having received three phase II Dengvaxia doses. These individuals, predominantly seronegative when vaccinated circulated low levels of DENV neutralizing antibodies which failed to protect mice against DENV 2

3 challenge.[13] The combination of poor protection against DENV infection of individuals circulating dengue antibodies (monotypic immune equivalents)

cr ipt

satisfies the known pre-conditions for antibody dependent enhancement of infection (ADE). [14]

2. Hospitalizations in vaccinated vs placebos. During year 3, based upon serological status and DENV infection rates measured in children in Asian vaccination sites,

us

the twenty hospitalized 2 – 5 year olds were estimated to among 176 seronegative vaccinated children who experienced their first DENV infection, a hospitalization

an

rate of 11.4%. [8, 12] In the corresponding placebo population it could be estimated there were 60 DENV monotypic-immunes who experienced secondary

M

DENV infections of whom 2 were hospitalized, or 3.3%, a rate similar to hospitalization rates reported for second DENV infections in many prospective cohort studies. [8, 14] The ratio, 3.5 x hospitalization of children sensitized by

pt ed

vaccine compared with those sensitized by a single prior DENV infection may persist into older age groups although at rates dictated by age-specific risk to the

DENV vascular permeability syndrome. [8, 15]

3. Hospitalizations in vaccinated and placebo groups occur in different populations.

ce

Among placebos, >/= 9 year-old children were hospitalized nearly twice as frequently as 2 – 5 year-olds, 3.1/1000 (27/17,346) vs 1.6/1000 (27/8703). [6]

Ac

This higher hospitalization rate for older compared with younger children corresponds to the age specific hospitalization rates in open populations due

predominantly to secondary DENV infections, in Asia peaking at 9 -11 years. [8, 16] In the vaccine cohort, 2 – 5 year-olds were hospitalized at a rate of 9.9/1000

4 (20/2029) compared with 1.6/1000 for >/= 9 year olds (27/17,346). [6] This 6-fold difference in the hospitalization rate of younger compared with older children

cr ipt

mirrors the higher intrinsic susceptibility of young compared with older children to hospitalizations during secondary DENV-2 infections in Cuba.[15]

4. Vaccine efficacy miscalculated. Standard vaccine efficacy calculations compare

disease attack rates in placebo groups with those in vaccinated groups. But, when

us

a vaccine has the potential to sensitize a recipient to immune enhancement, a

classical efficacy calculation is not relevant. In the vaccine group, seronegatives

an

may be converted by vaccine to “monotypic-immune equivalents” who experience disease/hospitalizations during breakthrough primary DENV

M

infections. Whereas hospitalizations in the placebo groups occur during secondary DENV infections. Thus, DENV hospitalizations in vaccinees and placebos occur in completely different denominator groups. These rates cannot be compared.

pt ed

5. Vaccine-enhanced dengue disease. The observed increased rate of hospitalization among vaccinated 2 – 5 year olds was labeled by SAGE as a “theoretical risk,” causally attributed among other possibilities to “temporal clustering.”[7] However, following transmission of DENV-1 in 1977, in Cuba, a clustered

ce

outbreak of DENV-2 in 1981, produced hospitalizations during secondary

infections while seronegative children experienced inapparent or mild

Ac

disease.[17] It must be concluded that among seronegative vaccinees, breakthrough dengue disease, certainly hospitalizations, that occur at rates significantly greater than those during primary dengue infections when

5 normalized for age should be scored as serious adverse events. “Clustering” of cases due to the vaccination of large numbers in cohorts is irrelevant.

cr ipt

Discussion:

An important element contributing to SAGE’s conclusion on Dengvaxia safety was that the risk of hospitalization for 2 – 5 year-olds peaked at year 3 and subsequently diminished or

“dissipated.” This conclusion is refuted by data from year 6 of the phase IIb trial. Table 8 from

us

the Background Paper on Dengue Vaccines shows that there were 37 hospitalizations among

2131 vaccinated children (vs 13 among 1072 placebos). The rates by age group when vaccinated

an

are: 2 – 5 yrs: 11/393 = 2.8%; 6 – 8 yrs: 15/945 = 1.6% and >/= 9 years: 11/793 = 1.4% (denominators from table 1 Hadinegoro et al. NEJM).[6] Calculated for vaccinated susceptibles the rates would be 2 – 5 times higher. Year 6 overall hospitalization rate of 37/2131 = 1.7% is

M

higher than that for year 3, 22/2131 = 1.0%. Hospitalizations are not “dissipating.” This increase in hospitalization rate may parallel increases in dengue disease severity observed with increasing

pt ed

interval between first and second DENV infections.[18] While SAGE has recognized that “the greatest benefit would be expected in those who are seropositive at the time of vaccination” it was concluded that “Currently, there is no rapid, point-of-care test to establish serostatus in order to allow for this kind of targeted vaccination.”

ce

And that “Any requirement to conduct seroprevalence studies prior to vaccine implementation will be new to the EPI programme.” [7] SAGE thus failed to rise to the unique challenge posed

Ac

by the need to identify and avoid the immunological risks imposed by the possible occurrence of vaccine-enhanced disease. Point of care lateral flow tests are on the market that would permit rapid identification of individuals circulating dengue IgG antibodies. Further, vaccine can be

6 administered in a two-step process whereby children have their ELISA dengue IgG status determined to be deemed vaccine-eligible or ineligible.

cr ipt

The report notes that “a statistically significant increased risk of hospitalized dengue was seen in (2-5 year-old) vaccine recipients in the third year after the first dose,” but concluded

simply that “this increased risk is currently not understood.” [7] Why not? The possibility that

vaccine enhanced disease occurred in individuals above and below 9 years of age should have

us

been subjected to careful scrutiny prior to vaccine licensure. To overcome the vacuum left by

incomplete pre-vaccination serological sampling, the immune status at the time of vaccination

an

can be identified retrospectively in vaccinated children who acquire a subsequent DENV infection. For example, the presence of anti-dengue envelope IgG but absence of dengue NS1

M

IgG antibodies in late convalescent sera characterizes a first dengue infection on a background of Dengvaxia yellow fever vaccine-derived immunity. Clarifying how populations with different immunological backgrounds handle dengue infection after Dengvaxia administration is crucial

pt ed

for regulatory authorities who must direct Dengvaxia delivery, whether via public or private channels, to optimize benefit and minimize risk. The SAGE Dengue Vaccine Working Group should consider the special assessments required to identify viral vaccine safety and measure efficacy where the vaccine itself may sensitize to ADE.

Ac

ce

Footnotes: The author has no conflicts of interest/funding to disclose.

7 References: 1. http://www.who.int/immunization/sage/meetings/2016/april/en/. Accessed 22 April 2016.

cr ipt

2. Guy B, Briand O, Lang J, Saville M, Jackson N. Development of the Sanofi Pasteur tetravalent dengue vaccine: One more step forward. Vaccine 2015; 33:7100-11.

3. Sabchareon A, Wallace D, Sirivichayakul C, et al. Protective efficacy of the recombinant, liveattenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet 2012; 380:1559-67.

us

4. Capeding MR, Tran NH, Hadinegoro SR, et al. 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 2014; 384:1358-65. 5. Villar L, Dayan GH, Arredondo-Garcia JL, et al. Efficacy of a Tetravalent Dengue Vaccine in Children in Latin America. N Engl J Med 2014; 372:113-23.

an

6. Hadinegoro SR, Arredondo-Garcia JL, Capeding MR, et al. Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. N Engl J Med 2015; 373:1195-206.

M

7. Secretariat SWGoDvaW. Background Paper on Dengue Vaccines. Geneva: World Health Organization 2016. 8. Halstead SB, Russell PK. Protective and immunological behavior of chimeric yellow fever dengue vaccine. Vaccine 2016; 34:1643-7.

2016.

pt ed

9. http://www.sanofipasteur.com/en/articles/dengvaxia-world-s-first-dengue-vaccine-approvedin-mexico.aspx

10. http://outbreaknewstoday.com/el-salvador-becomes-the-4th-country-to-approve-denguevaccine-53510/, 2016. 11. http://www.scientificamerican.com/article/first -dengue-fever-vaccine-gets-green-light-inthree-countries/, 2016.

ce

12. Coudeville L, Baurin N, Vergu E. Estimation of parameters related to vaccine efficacy and dengue transmission from two large phase III studies. Vaccine 2016; doi: 10.1016/j.vaccine.2015.11.023. [Epub ahead of print.

Ac

13. Velumani S, Toh YX, Balasingam S, et al. Low antibody titers 5 years after vaccination with the CYD-TDV dengue vaccine in both pre-immune and naive vaccinees. Hum Vaccin Immunother 2016; 12:1265-73.

14. Halstead SB. Neutralization and antibody dependent enhancement of dengue viruses Adv Virus Research 2003; 60:421-67. 15. Guzman MG, Kouri G, Bravo J, Valdes L, Vazquez S, Halstead SB. Effect of age on outcome of secondary dengue 2 infections. International J Infectious Diseases 2002; 6:118-24.

8 16. Anders KL, Nguyet NM, Chau NV, et al. Epidemiological factors associated with dengue shock syndrome and mortality in hospitalized dengue patients in Ho Chi Minh City, Vietnam. Am J Trop Med Hyg 2011; 84:127-34.

cr ipt

17. Guzman MG, Kouri GP, Bravo J, Soler M, Vazquez S, Morier L. Dengue hemorrhagic fever in Cuba, 1981: a retrospective seroepidemiologic study. AmJTropMedHyg 1990; 42:179-84.

Ac

ce

pt ed

M

an

us

18. Guzman MG, Kouri, G., Valdes, L., Bravo, J., Vazquez, S., Halstead, S.B. Enhanced severity of secondary dengue 2 infections occurring at an interval of 20 compared with 4 years after dengue 1 infection. PAHO Journal of Epidemiology 2002; 81:223-7.

Suggest Documents