Yellow Fever Vaccine Fractional Dosing for Travellers – A South African Experience
Travel Doctor Corporate, Johannesburg, South Africa,
Travel Doctor, Johannesburg, South Africa
University of the Witwatersrand, Johannesburg, South Africa,
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Our study documents the provision of fractional yellow fever vaccine in a travel clinic setting, and the outcome in terms of adverse effects in the immediate period following administration. Our study also demonstrates the importance of meticulous record keeping when using vaccines off label.
In July 2022 South Africa experienced a severe, indefinite yellow fever vaccine shortage. After considering published evidence for the use of fractional yellow fever vaccine dosing from the WHO and Canadian CATMAT, the South Society of Travel Medicine (SASTM) issued a directive for the use of fractional yellow fever vaccine to its members. Our travel clinic primarily provides comprehensive corporate travel health risk management to employees who travel for work. In addition, we see a large number of leisure travellers. In the wake of the COVID-19 pandemic South Africans were desperate to find employment abroad, often in yellow fever affected countries. Proof of yellow fever vaccination is a public health requirement for travellers from yellow fever affected countries to South Africa.
Fractional dosing allows vaccinating 4-5 times more travellers than standard dose. When the shortage was announced, we took stock of our yellow fever vaccine supply and instituted fractional dosing. We documented demographic data for clients receiving fractional doses and their destination country. All clients were provided with the option of seeking a full dose elsewhere or postponing travel. Clients who chose to receive fractional dosing signed informed consent and were informed to return for a full dose after one year, as per SASTM protocol, or whenever travelling to a yellow fever affected country, once yellow fever vaccine became available again. All requests for yellow fever vaccine were screened to determine the actual need for vaccination, e.g., travellers who only required proof of vaccination as an assurance in the event of an unscheduled transit of more than 12 hours through a yellow fever affected country, were discouraged from taking a fractional dose.
Unlike the Canadians who did not issue their fractional dose recipients with an ICVP but only provided them with a letter stating that they had received a fractional dose and should return for a full dose when possible, we did provide an ICVP. We did not however certify that the fractional dose was “valid for life” but indicated that it was only valid for one year from the date of administration.
We note that the WHO condones the use of fractional dosing but not issuing an ICVP in such cases to travellers. The SASTM Exco however, decided that there is a very high likelihood that letters indicating vaccination, not on an ICVP and in the correct format, but on a letter, would be rejected by port health authorities.
This is not unique in that some countries in e.g. Europe indicate a first full yellow fever vaccine dose as valid for 10 years and only certify a second dose as “valid for life”. This is also not in line with WHO policy but a practical way to ensure that travellers who may need a second dose, do return after ten years.
We administered 525 fractional doses over a three-month period. We did follow up calls to all fractional dose recipients and recorded possible side effects in five clients.
Of the 525 vaccines administered 59% of recipients were male and 41% were female.
87% were between the ages of 21 and 60 years of age. Majority within the working age.
Saudi Arabia – declared requirement for travellers from South Africa in spite of South Africa not being yellow fever affected
Tanzania; Zambia; Rwanda – employer requirement
Sub-Saharan Africa was the most common destination, followed by South America.
428 clients travelled for work, of which 27 were seafarers.
We were informed by an infectious disease specialist that he admitted a patient with a possible severe adverse event for investigation. This event prompted an active follow up campaign of all fractional dose recipients. Our experience reinforced the importance of accurate contact details. We did not receive reports of any problems with border crossings because of the way the fractional dose was recorded on the ICVP.
Yellow fever is a viral disease that is transmitted by infected mosquitoes. While the disease is preventable through vaccination, there are regular or perceived global shortages of yellow fever vaccine. Supply to South Africa is limited and this led to a complete stock out in July 2022. Since then, including at the time of publication, there have been several more shortages due to a number of factors. To address both shortages and outbreaks, fractional dosing of the vaccine has been previously proposed as a potential solution for public health focused vaccine drives by the WHO during major outbreaks in affected countries and by CATMAT in Canada during a vaccine shortage, for travellers.
The only yellow fever vaccine available in South Africa is supplied in a vial containing ± 0,5ml of reconstituted vaccine.
Several studies have been conducted to assess the efficacy and safety of fractional dosing of the yellow fever vaccine. A study conducted in Senegal found that fractional dosing of the vaccine was effective in providing immunity against yellow fever, with a seroconversion rate of 97.7% Another study conducted in Ghana found that fractional dosing of the vaccine provided similar levels of immunity as the standard dose, with a seroconversion rate of 98.1%.
While fractional dosing of the yellow fever vaccine has been shown to be effective, there have been concerns about the safety of this approach. Some studies have suggested that fractional dosing may be associated with an increased risk of adverse events, such as fever and headache. However, other studies have not found any significant differences in adverse events between fractional dosing and the standard dose.
A major question arises when using fractional dosing of the yellow fever vaccine: how long does immunity last? We know from the study done in the Netherlands in 2018 which followed 75 participants who had received the 0.1ml fractional dose 10 years prior, that 98% of participants still had protective levels of antibodies. The conclusion of this study showed that intradermal administration of a one-fifth dose of yellow fever vaccine induced a protective immune response that lasted for 10 years after vaccination and that persons receiving a fractional dose of yellow fever vaccine do not require a booster vaccination for long-term protection against yellow fever. However, the numbers studied were small.
Similar studies showed reassuring results of seropositivity at 10 years, however confirmation is required in larger populations including young children living in yellow fever endemic areas, immunocompromised individuals and older participants with comorbidities. A meta-analysis done in 2020 with a total of 2 371 participants, showed seroconversion rates at four to five weeks following vaccination were similar between participants who received standard doses and participants who received fractional doses containing one-third of the standard dose. However, the rates of seroconversion were substantially lower among participants who received fractional doses containing one-hundredth and lower fractions of the standard dose. Of those who seroconverted, immunogenicity similarly persisted 8-10 years following both fractional and standard dose vaccination.
In our study, most of the recipients of the fractional yellow fever dose (82%) were traveling for work. This meant extended periods of stay in yellow fever affected areas with prolonged exposure. Most of these were in West Africa, considered to be a high risk area. Proof of yellow fever vaccination is a Port Health Authority for persons entering South Africa from yellow fever affected countries. Depriving these workers of the opportunity to gain employment due to the lack of stock of yellow fever vaccine would have massive financial ramifications. For this reason, fractional dosing was a quick and simple solution to the shortage.
Good record keeping is essential in any travel clinic. During our campaign it was even more important as we were administering the vaccine off-label. The importance of this became even more obvious when we were made aware of the possible severe adverse event involving one of our recipients.
When we launched our follow-up initiative, we faced multiple record keeping challenges (see below) due to clients using incorrect/fake phone numbers and email addresses or simply filling in their data incompletely. Of the 525 patients who received fractional doses 45% were unreachable.
Number of days since receiving fractional dose of yellow fever
Of the 286 candidates who were reachable 286 were unaffected; five reported mild symptoms and there was one possible severe adverse event, the one described below. We found no evidence of significant adverse effects in any of the travellers we managed to contact. The following diagram demonstrates that there is a small possibility that we MAY have missed some adverse events.
We were contacted by an infectious diseases specialist on 4 September 2022. He admitted a 40-year-old female, about two weeks after she received a fractional dose of yellow fever vaccine. She had a five day history of fever, night sweats, headache, no neck stiffness. The extensive workup done (nasopharyngeal swabs, blood work, CT chest, MRI, lumbar puncture) was all negative. She was placed on Rocephin and Azithromycin, discharged home for 5 days and readmitted with fatigue and fever when she came into the care of the infectious diseases specialist who traced her vaccine to our clinic. After extensive workup, yellow fever vaccine associated viscerotropic disease was excluded as the diagnosis. This incident did however emphasise the importance of accurate record keeping and informed consent. The patient made an uneventful recovery.
Fractional yellow fever vaccine dosing is a safe and effective solution in the event of short-term vaccine shortage.
Our experience emphasises the importance of meticulous record keeping in the travel clinic setting.
Current research suggests that fractional dosing has a similar safety profile to the standard dose and is effective in providing immunity against yellow fever up to one year in travellers and as long as ten years given the recipient was healthy at the time of vaccination. Fractional dosing has already been shown to be effective in the control of outbreaks.
Further studies are needed to establish the long-term immunity of fractional dosing in a wide range of travellers. In the face of potential global yellow fever vaccine shortages further studies should be conducted to determine the optimal dosing strategy for the yellow fever vaccine in the future.
- World Health Organization. (2016). Fractional dose yellow fever vaccine as a dose-sparing option for outbreak response: WHO Secretariat information paper. World Health Organization.
- Government of Canada. (2016). Interim recommendations for the use of fractional-dose yellow fever vaccine during a vaccine shortage. Yellow Fever Working Group, the Committee to Advise on Tropical Medicine and Travel (CATMAT). Retrieved from https://www.canada.ca/en/public-health/services/publications/diseases-conditions/interim-recommendations-fractional-dose-yellow-fever-vaccine-shortage.html.
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- Nnaji, C. A., Shey, M. S., Adetokunboh, O. O., & Wiysonge, C. S. (2020). Immunogenicity and safety of fractional dose yellow fever vaccination: A systematic review and meta-analysis. Vaccine, 38(3), 430-439. doi: 10.1016/j.vaccine.2019.12.018
- Roukens, A. H. E., van Halem, K., de Visser, A. W., & Visser, L. G. (2018). Long-Term Protection After Fractional-Dose Yellow Fever Vaccination: Follow-up Study of a Randomized, Controlled, Noninferiority Trial. Annals of Internal Medicine, 169(11), 761-762. doi: 10.7326/M18-1529