Comparative safety and immunogenicity of two yellow fever 17D vaccines (ARILVAX and YF-VAX) in a phase III multicenter, double-blind clinical trial.

Abstract

Abstract. Yellow fever (YF) is a significant health problem in South America and Africa. Travelers to these areas require immunization. The United States, infested with Aedes aegypti mosquitoes, is at risk of introduction of this disease. There is only a single U.S. manufacturer of YF 17D vaccine, and supplies may be insufficient in an emergency. A randomized, double-blind outpatient study was conducted in 1,440 healthy individuals, half of whom received the U.S. vaccine (YF-VAX) and half the vaccine manufactured in the United Kingdom (ARILVAX). A randomly selected subset of approximately 310 individuals in each treatment group was tested for YF neutralizing antibodies 30 days after vaccination. The primary efficacy endpoint was the proportion of individuals who developed a log neutralization index (LNI) of 0.7 or higher. Seroconversion occurred in 98.6% of individuals in the ARILVAX group and 99.3% of those in the YF-VAX group. Statistically, ARILVAX was equivalent to YF-VAX (P ‫ס‬ .001). Both vaccines elicited mean antibody responses well above the minimal level (LNI 0.7) protective against wild-type YF virus. The mean LNI in the YF-VAX group was higher (2.21) than in the ARILVAX group (2.06; P ‫ס‬ .010) possibly because of the higher dose contained in YF-VAX. Male gender, Caucasian race, and smoking were associated with higher antibody responses. Both vaccines were well tolerated. Overall, the treatment groups were comparable with respect to safety except that individuals in the ARILVAX group experienced significantly less edema, inflammation, and pain at the injection site than those in the YF-VAX group. No serious adverse events were attributable to either vaccine. YF-VAX participants (71.9%) experienced one or more nonserious adverse events than ARILVAX individuals (65.3%; P ‫ס‬ .008). The difference was due to a higher rate of injection site reactions in the YF-VAX group. Mild systemic reactions (headache, myalgia, malaise, asthenia) occurred in roughly 10% to 30% of participants during the first few days after vaccination, with no significant difference across treatment groups. Adverse events were less frequent in individuals with preexisting immunity to YF, indicating a relationship to virus replication.

Reactogenicity of yellow fever vaccines in a randomized, placebo-controlled trial

“…That converges with data from two previous studies. 5,10 Others 14,18 found small elevations in AST, ALT and GGT, but lacked unvaccinated controls.…”

“…3 The frequency of signs and symptoms on the injection site reported in the literature varied from nil to 39%. 5,7,[9][10][11]14,15,17,18,20,22,23 In all studies, pain on the site of injection was the most frequently reported local adverse event. The highest frequencies of adverse events were based on diaries, which could inflate the frequency by stimulating reports of trivial signs/symptoms.…”

“…The highest frequencies of adverse events were based on diaries, which could inflate the frequency by stimulating reports of trivial signs/symptoms. 5,7,9,10,14,16,22 The location, timing and nature of signs and symptoms on the site of vaccine injection make it easier to associate them with immunization. Placebo components are known to be able to cause local discomfort and the proportion of local reactions in placebo controls allowed a rough approximation of the role of that vaccine component (Table 1).…”

“…5,10 Nevertheless, figures as high as 41% and as low as 7.6% have been reported. 9,14 It is difficult to determine to what extent methodo-www.fsp.usp.br/rsp Reactogenicity of yellow fever vaccines Camacho LAB et al logical differences rather than genuine reactogenicity explained the performance of YF vaccines in the studies above. They varied in the age of subjects, sample size, type of vaccine (virus content, stabilization), site of inoculation (arm, thigh, interscapular region), level of inoculation (subcutaneous injection, jet injector), method of ascertainment (questionnaire, diary, physical examination, including measurement of body temperature and inspection of site reactions and lymphadenopathy), and simultaneous administration of other vaccines (measles, cholera, smallpox, hepatitis A), or drugs (chloroquine).…”

The pathogenesis of dengue

“…Japanese encephalitis virus and Yellow Fever, where the accepted vaccine-elicited correlate of immunity is virus-neutralizing antibody. [28][29][30][31] Confirmation that virus neutralizing antibody is a correlate of dengue immunity is most likely to come Sabin demonstrated in the post-war era how infection with one serotype gave long-lasting protection to that specific serotype (homotypic immunity) and short-lived protection against the other serotypes (heterotypic immunity). 33 The basis for homotypic immunity is believed to be virus-neutralizing antibodies.…”