Yellow fever vaccine – past, present & future

YELLOW FEVER VIRUS
Arbovirus
Family – Flaviviridae
Genus – Flavivirus
Single serotype
Reservoir - Monkeys
Vector – Aedes Aegypti
Endemic to Africa & South America
No specific anti-viral treatment
Vaccination

PAST
1912 – opening of Panama canal – increased global exposure – first modern attempt for vaccine development

Hideyo Noguchi, a Japanese bacteriologist – worked for Rockefeller Foundation, Ecuador – Vaccine based on disease caused by leptospiral bacterium.
Resulting vaccine – ineffective – eventually abandoned.

“French strain” – obtained from a survivor – another vaccine by Pasteur Institute scientists.
Administered by scarification, like smallpox vaccine – given in combination – immunity to both diseases.
But severe systemic and neurologic complications were observed.

Attempts to attenuate – failed.
Another vaccine developed – derived from Asibi in 1927.
First isolation from human.
Safer
Limited widespread use – due to use of large amount of human serum.

In 1937, Max Theiler (awarded the Nobel Prize in Physiology or Medicine in 1951 for developing a vaccine against yellow fever) with Hugh Smith & Eugen Haagen at the Rockefeller Foundation to improve the vaccine from the "Asibi" strain, discovered that a favorable chance mutation in the attenuated virus had produced a highly effective strain that was named 17D.

Theiler used chicken eggs to culture the virus.
Over 1 million people vaccinated by 1939 – after brazil field trials.
Widely used by U.S. Army during WW-II.

Theiler’s vaccine – largest outbreak of Hepatits B – 330,000

In 1941 – “aqueous-base” version of 17D vaccine – distilled water combined with virus grown in chicken eggs.

PRESENT
Currently available YF-vaccines (WHO prequalified)
Bio-manguinhos, 17-DD, Brazil
Sanofi Pasteur, Stamaril, 17D-204, France
Pasteur Institute Dakar, 17D-204, Senegal
Chumakov Institute, 17D-204, Russian federation
Sanofi Pasteur, YF-Vax, 17D-204, USA

Contraindiction
Allergy to vaccine component (Egg protein)
Age < 6 months
Symptomatic HIV infection/CD4+ counts < 200 per mm^3
Thymus disorder
Primary immunodeficiencies
Malignant neoplasms
Transplantation
Immunosupressive and immunomodulatiory therapies
Precaution
Age 6-8 months
Age ≤ 60 yrs
Asymptomatic HIV & CD4+ counts 200-499 per mm^3
Pregnancy
Breast feeding

Common adverse events of YF Vaccines
Fever, headache, backache 3-7 days after vaccination: 5-15%
Injection site inflammation 1-5 days after vaccination: 1-30%

WHO YF vaccines recommendations:
SAGE formed YF Vaccine workgroup in 2011: Need for booster dose every 10 years to maintain protection against yellow fever
Safety of YF Vaccine in selected special populations
Co-administration of YF and other vaccines
Single subcutaneous dose IHRs require revaccination at intervals at 10 yrs to boost antibody titers

YF VACCINE ASSOCIATED DISEASE
Neurogenic- due to direct viral invasion of CNS or auto-immune mediated, can lead to most common meningoencephalitis
Others – GBS, ADEM, Bulbar palsy, Bell’s palsy
Onset median- 11 days post vaccination
2. Viscerotrophic disease
Severe illness similar to wild-type disease
Onset median – 3 days post vaccination
Tend to affect younger females and older males
63% fatality rate

WHO EYE INITIATIVE
“Eliminate Yellow Fever Epidemics”
Aims to increase 17D vaccine manufacturing to distribute 1.3 billion vaccine doses to endemic countries by 2026.

FUTURE
Present issues to be solved to prevent future epidemics:
Finite vaccine seed-lot system
Limited vaccine manufacturing capabilities using embryonated chicken eggs
Climate change pushing mosquito habitats to new regions
Recent epidemics exposing issues in rapid vaccine dissemination
Storage problems

Solutions
A more shelf-stable vaccine - more doses generated with fewer IU per dose
YF-Vaccines in development and their benefits:
inactivated vaccines - allow those over 60 to receive a primary dose of vaccine (Eg. XRX-001 vaccine highly immunogenic with antibody titers similar to live-17D vaccine)
recombinant vaccine constructs - higher immunogenicity with lower dose and least side-effects (Eg. 105 TCID50)
plasmid-vectored DNA constructs – quick production of neutralizing antibodies
virus-like particles (VLPs) – replication incompetent
mRNA vaccines – fast manufacturing
Synonymous mutations in live-attenuated vaccines - Deoptimizing multiple codons can attenuate viruses, as well as lower the risk of reversion and recombination of the attenuated virus
Plant-produced subunit vaccines – reduce dependence on chicken embryo culture, using Nicotiana benthamiana (in progress)