Live Attenuated Human Hookworm Vaccine Shows Promise

A live attenuated human hookworm vaccine was well tolerated and elicited humoral and cellular immune responses to hookworm antigens, according to results of a small study published in Lancet Infectious Diseases.

This phase 1 study conducted in Australia was a 2-part clinical trial evaluating the safety, tolerability, and immunogenicity of a live attenuated Necator americanus larvae vaccine. Part 1 of the study assessed dosing among 7 healthy adults who were inoculated with ultraviolet C (UVC)-treated N americanus third-stage larvae (L3). Part two was a randomized, doubleblind, placebo-controlled challenge study in which 15 participants were randomly assigned in a 2:1 fashion to receive either 2 doses of the attenuated larvae vaccine or placebo and then challenged with unattenuated N americanus larvae.

The primary outcome of the dose-finding study was the level of larval attenuation that resulted in a grade 1 or 2 dermal adverse reaction. The primary outcome of the challenge study was the frequency and severity of adverse events between the vaccinated and placebo groups after vaccination and challenge phase. Exploratory outcomes included humoral and cellular immunological markers of exposure to hookworm antigens.

To ensure that any infection was eliminated, a single 400-mg dose of oral albendazole was administered 4 weeks after each inoculation and 6 weeks after the second vaccination. In addition, a 3-day course of albendazole was initiated on day 161 after the challenge phase.

In the dose-finding study, 7 participants, of whom86% were White and 86% were women, received 50 L3 attenuated with either 700 μJ of UVC (L3-700; n=4) or 1000 μJ of UVC (L3-1000; n=3). Compared with the L3-1000 group, the L3-700 group had greater number of skin penetration sites (mean, 15.75 vs 4.33), greater erythema (median, 225 vs 25 mm²), and an increased duration of dermal reaction (median, 8.0 vs 2.0 days). All participants reported grade 1 adverse events, and L3-700 was used for the vaccination in the challenge study.

Among the 15 participants included in the challenge study, of whom 93% were White and 73% were men, 10 received L3-700 and 5 received placebo in the form of tabasco sauce to imitate skin reaction caused by dermal hookworm inoculation. Following vaccination, the L3-700 group experienced an increase in adverse events compared with the placebo group (mean, 8.1 vs 3.8; incident rate ratio [IRR], 2.13; 95% CI, 2.09-5.51; P =.0030). However, following the challenge phase, there was no difference in the frequency of adverse events between the 2 groups (mean, 6.0 vs 4.8; IRR, 1.25; 95% CI, 0.78-2.01; P =.36). Most adverse events were mild, with only 1 severe adverse event reported in the vaccine group.

Compared with participants in the placebo group, those in the vaccine group had fewer larvae per gram of feces recovered (median, 0.8 vs 10.2; P =.014). “Although the median concentration of N americanus DNA in the feces of participants [in the placebo group] was slightly higher than that of vaccinated participants, the difference was not significant,” noted the researchers.

On day 161, an exploratory analysis performed after the challenge phase showed that while eosinophil counts increased among all participants, those in the vaccine group had a significantly greater median increase vs those in the placebo group (1.55 × 10⁹ vs 0.49 × 10⁹ cells/L; P =.014). Participants in the vaccine group also had increased immunoglobulin G (IgG) titers in response to larval extract vs those in the placebo group (IgG titers, 0.22 vs 0.03; P =.020).

Analysis of hookworm antigen-specific cytokine responses 28 days after the challenge phase by peripheral blood mononuclear cells showed that participants in the vaccine group had significantly increased production of interferon gamma, tumor necrosis factor alpha, interleukin (IL)-2, IL-4, and IL-5, but not IL-10.

This study was limited by its small sample size and the lack of an active comparator group.

Although larger studies are required, results of this study “provide robust proof of concept that controlled human hookworm infection can be used to assess the efficacy of hookworm therapeutics,” the researchers concluded.

Reference

Chapman PR, Webster R, Giacomin P, et al. Vaccination of human participants with attenuated Necator americanus hookworm larvae and human challenge in Australia: a dose-finding study and randomised, placebo-controlled, phase 1 trial. Lancet Infect Dis. Published online August 19, 2021. doi:10.1016/ S1473-3099(21)00153-5