Vanessa Studans-Shideler

Biology 1615
Tues Noon
Summary of the randomized, double-blind, phase III, pivotal field trial of the comparative
immunogenicity, safety and tolerability of two yellow fever 17D vaccines (ARILVAX and
YF-VAX) in healthy infants and children in Peru
Yellow fever (YF) is a hemorrhagic fever spread by mosquitoes mostly in tropical regions
of South America and Africa. YF is related to the family Flaviviridae which are single stranded
RNA viruses that includes dengue and West Nile viruses. YF infections can be relatively minor
to severe and can include hepatitus, renal failure, bleeding diatheses, and cardio vascular
collapse. The World Health Organization (WHO) has estimated that 200,000 cases occur in
these endemic areas each year and that the fatality rate is between 20-50%.
A YF vaccine was first developed in 1936. More than 400 million people have been
immunized since 1937, however, given this large number, no controlled clinical studies have ever
been conducted on the efficacy and safety of these vaccines in children and infants. Despite this
lack of study, this demographic represents a large body of the population being vaccinated in
these endemic areas.
The two vaccines studied were ARILVAX AND YF-VAX. Both of these have
demonstrated mild (erythema, swelling, and pain at the injection site) and systemic reactions
(feeling ill, headache, myalgia, and fever with or without symptoms) as occurring in a small
number of adults. Since 2000 the Peruvian Ministry of Health has recommended that all children
be vaccinated beginning at the age of nine months of age. Despite this recommendation
however, the implementation of this has not been consistant largely due to a shortage in vaccine.

Rates of vaccination is also affected by regions, as some regions exhibit more risk of
transmission than others. Peru has the highest transmission rates.
Both of the vaccines studied are manufactured in embryonated chicken eggs and both
vaccines meet the international standards and requirements of YF vaccines as outlined by WHO.
While there are minor differences in the final formulations of the two vaccines, the two are
greater than 99% homologous at the nucleotide sequence level.
The City of Sullana, Peru was chosen as the location for the clinical trial because less
than 3% of the age eligible children had received YF vaccine. Moreover, Sullana is within 100
miles of areas in which reports of infection have occurred as well as the city being infested by
Aedes aegypti mosquito (the principal transmitter).
1,107 healthy children (9 months to 10 years of age) in Sullana, Peru were chosen to
conduct this randomized, double-blind, phase III vaccine trial. The objectives were to determine
the safety, tolerability and efficacy of ARILVAX AND YF-VAX. The study also assessed the
consistency in three different batches of ARILVAX. Research was conducted under an
Investigational New Drug Application as approved by the FDA and followed Good Clinical
Practice regulations and clinical research guidelines. Five clinics were chosen to administer the
study based upon staff availability and other logistical concerns. Two groups of children were
established, the nine months to five years of age category, and the 5-10 years of age category. A
2:1 ratio of ARILVAX TO YF-VAX was followed with 738 children receiving ARILVAX and
369 receiving YF-VAX.
Enrollment in the study was limited to infants and children meeting certain criteria.
Criteria that would exclude them from participation were: children that fell outside of the age

parameters, those who were ill or had poor growth or children that had received another
vaccination in the previous 30 days. Children who had histories of egg allergies were excluded.
Also, children who had already received a YF vaccination were excluded from participating in
the study (established through their immunizations records).
Study protocol was for sera samples to be taken on days 1 and 31. Sera was tested for
neutralizing antibodies to YF, the principal way immunity by YF vaccines has been proven to
correlate. Sera tested on day 1 established whether the child already displayed YF immunity
prior to vaccination. Testing on day 31 confirmed immunization after vaccination. The primary
goal of the study was to establish that the vaccines were equal in the immunogenicity, and more
specifically that ARILVAX was not inferior to YF-VAX. Non-inferiority was determined as
having a clinically acceptable difference of no more than 5%. The secondary goal was to
compare the geometric mean titers (GMT) between the two vaccine groups. Clinical consistency
of the 3 production lots of ARILVAX was established by comparing the geometric YF
neutralization titer for homogeneity. The safety as well as tolerability were analyzed by
comparing the incidence of adverse effects (AE) across the two treatment groups.
The baseline established had 36 children who were found to be YF immune at the
beginning of the study, 82 did not have two samples taken for serologic testing, 1 child had a
baseline titer that could not be determined and 7 children did not complete the protocol. This
leaves the study with a final sample of 981 for final analysis.
Overall 94.9% of the ARILVAX and 90.6% of the YF-VAX recipients demonstrated
immunity to YF at the conclusion of the study. This rate demonstrated that ARILVAX was not
inferior to YF-VAX and established the primary goal of the study. In fact, the statistical study,

without going in to details of that portion of the research, showed that ARIVAX actually
produced a higher response rate than YF-VAX. Moreover, the study found that there was no
difference between the two vaccines in their antibody titer response. The tests for ARILVAX
production lot consistency showed that there was equivalency in the 3 lots. The number of
children that seroconverted to each lot was very similar in range.
No significant adverse effects (SAE) were experienced by children vaccinated by either
ARILVAX or YF-VAX. There were 2 children who had 3 unrelated SAE's after YF-VAX. The
incidences of AE's between the two study groups was nearly identical. The majority of AE's
reported were mild and were said to have cleared up within 24-48 hrs post-vaccination. The
majority of the AE's reported were similar between the two vaccinations and most were common
pediatric conditions. Interestingly, given the age range of the study subjects, it is thought and
accepted that underreporting most probably occurred because of the mild nature of the AE's.
Durability of the vaccination could not be established because enough time has not
passed, however, both vaccinations in adults have been shown to last more than 35 years.
Although the seroconversion rates in children was high, it is generally higher in adults. It is still
unclear as to why the difference between children and adults. There are some factors that can
affect an immune response to the vaccination. These are 1) pre-existing immunity to related
flaviviruses such as dengue viruses, 2) immunosuppression due to pre-existing diseases or drug
treatments, 3) severe malnutrition, and 4) pregnancy.
There is overlap in South America with YF and dengue transmission. For this reason the
study did look at dengue immunity to find out if this affected the immune response to YF
vaccine. The evidence collected appears to suggest that the YF antibody response was higher in

children that were dengue immune after the vaccine than among child not dengue-immune. This
suggests flavivirus antigenic cross-reactivity. The study concluded that this dengue-immunity
deserves further study as it is of particular importance in Peru and South American countries.

It

has been suggested since as early as 1923 that dengue immunity may be a reason for YF
immunity in endemic areas.
Until this study, no other studies had been conducted on the efficacy of ARILVAX and
YF-VAX on infants and children. This study concluded that the two vaccines were effective and
well tolerated by the pediatric groups. Because of the results, if approval is established,
ARILVAX will be sold in the United States to travelers, medical personnel and military.

Bibliography
Belmusto-Worn, Vivian. "Randomized, double-blind, phase III pivotal field trial of the
comparative immunogenicity, safety, and tolerability of two Yellow Fever 17D Vaccines
(ARILVAX and YF-VAX) in healthy infants and children in Peru." The American Society of
Tropical Medicine and Hygiene 72(2),2005, pp. 189-197