Questions regarding the safety and duration of immunity following live yellow fever vaccination

Abstract

The World Health Organization (WHO) and other health agencies have concluded that yellow fever booster vaccination is unnecessary since a single dose of vaccine confers lifelong immunity. Areas covered: We reviewed the clinical studies cited by health authorities in their investigation of both the safety profile and duration of immunity for the YFV-17D vaccine and examined the position that booster vaccination is no longer needed. We found that antiviral immunity may be lost in 1-in-3 to 1-in-5 individuals within 5 to 10 years after a single vaccination and that children may be at greater risk for primary vaccine failure. The safety profile of YFV-17D was compared to other licensed vaccines including oral polio vaccine (OPV) and the rotavirus vaccine, RotaShield, which have subsequently been withdrawn from the US and world market, respectively. Expert commentary: Based on these results and recent epidemiological data on vaccine failures (particularly evident at >10 years after vaccination), we believe that current recommendations to no longer administer YFV-17D booster vaccination be carefully re-evaluated, and that further development of safer vaccine approaches should be considered.

Keywords: Yellow fever virus; antibody duration; flaviviruses; immunity; neurotropic; vaccination; viscerotropic.

Figure 1. YFV-17D-specific T cells fail to protect against infection in the absence of neutralizing antibodies

Clinical studies were conducted to determine if pre-existing YFV-specific immunity would impact virus replication upon challenge with YFV-17D or chimeric versions of YFV-17D in which the prM (pre-membrane) and envelope (Env) proteins of YFV-17D were replaced with either JEV [32] or DENV2 [31]. These recombinant viruses, ChimeriVax-JE and ChimeriVax-DEN2, were composed of the YFV-17D capsid (C) structural protein and 7 YFV-17D non-structural proteins, but could no longer be neutralized by YFV-17D-specific antibodies. This provided the opportunity to determine the impact of T cell-mediated protection in the absence of a neutralizing antibody response. YFV-17D infection elicits T cells to both structural and nonstructural proteins [23,24] but pre-existing antiviral T cell memory had no measurable impact on the peak or duration of viremia as determined by area-under-the-curve measurements [31,32,34].

Figure 2. Neutralization titers after yellow fever vaccination with 17D (n = 209)

Serum plaque reduction neutralizing titers (PRNT₉₀) were determined at the indicated time points following vaccination with YFV-17D. Neutralizing titers of >1:10 indicated a protective level of immunity. Neutralizing titers of 1:10 were considered borderline and titers of <1:10 were considered negative and both are highlighted in red. Adapted with permission from [27].

Figure 3. Models of host-pathogen interactions and potential impact on long-term immunity

Live virus vaccines may elicit different patterns of serum antibody maintenance based on pathogen-specific or host-specific differences in replication and overall antigen load. (A) The smallpox vaccines, Dryvax and MVA (Modified Vaccinia Ankara), are closely related strains of vaccinia virus that differ in their attenuation and ability to replicate in the human host. Dryvax is able to replicate locally in the skin for several days or weeks after inoculation and this induces a long-lived immune response in the majority of vaccine recipients [49,50]. MVA is replication-deficient and the virus is rapidly cleared, resulting in lower antibody responses that decay more rapidly than that observed with Dryvax [52,53]. (B) YFV-17D vaccine strains of virus elicit a viremic infection of variable magnitude and duration [56]. Approximately 70% of vaccine recipients achieve long-term, potentially lifelong immunity whereas ~30% of individuals lose antiviral antibody responses within 5 to 10 years after vaccination [27]. Since YFV-17D is genetically stable, one hypothesis is that differences in host susceptibility to YFV-17D infection represent an underlying factor that influences the magnitude and duration of the acute viral infection, and in turn, the differences in viral replication and systemic antigen load result in either short-term or long-term antiviral immunity.

Figure 4. Proportion of yellow fever cases in relation to YFV-17D vaccination history

The vaccine status of 831 cases of sylvatic yellow fever from 1973 – 2008 were reported in Brazil [3]. In 45% of the cases (372/831), vaccine status of the patient was unknown. Of the remaining cases, 52% of patients (432/831) had been vaccinated >10 years earlier and 3% (27/831) of patients had been vaccinated <10 years prior to disease onset. All cases of yellow fever were virologically confirmed and the case fatality rate was 51%.