Date: 10.07.2023

VLA15, a new global Lyme disease vaccine undergoes clinical trials

Lyme disease (Lyme borreliosis) is a tick-borne bacterial infection that occurs in the temperate climates of North America and Eurasia. Treatment with antibiotics is effective only in the early stages of infection. Although the first human Lyme disease vaccine (LYMErix by SmithKline Beecham, Pittsburgh, PA, USA) was marketed and distributed in the USA from 1998 until 2002, it was discontinued and no vaccine is currently available. In The Lancet Infectious Diseases, Nicole Bézay and colleagues report the results of a randomised, phase 1, clinical trial in healthy adults immunised with Valneva's novel, multivalent outer surface protein A (OspA) subunit vaccine called VLA15.

Hajdušek O., Perner J. 2023: VLA15, a new global Lyme disease vaccine undergoes clinical trials. Lancet Infectious Diseases 23: (in press). [IF=56.3] DOI: 10.1016/S1473-3099(23)00312-2

The earlier LYMErix vaccine was limited by its monovalency, containing only a single Borrelia burgdorferi OspA antigen. In contrast, VLA15 is a multivalent vaccine that contains OspA C-terminals from multiple clinically relevant Borrelia species from North America (B burgdorferi) and Europe (B burgdorferiBorrelia afzeliiBorrelia garinii, and Borrelia bavariensis). The VLA15 vaccine consists of three lipidated OspA heterodimers (reflecting six Borrelia OspA serotypes) expressed in Escherichia coli and formulated with an alum adjuvant.

This vaccine no longer contains the problematic epitope that was present in the LYMErix vaccine and which was thought to be associated with the development of autoimmune arthritis through a cross-reaction with human leukocyte function-associated antigen (hLFA1) . Although the link between the LYMErix vaccine and arthritis has since been disproven, disclosure of the problem contributed to loss of confidence in the vaccine and eventually to the voluntary withdrawal of LYMErix from the market.
In the study reported here, which was done in Europe and the USA between 2017 and 2019 in 179 healthy adults (aged ≥18 to <40 years), Bézay and colleagues evaluated the safety, tolerability, and immunogenicity of VLA15 by administering three intramuscular injections 1 month apart, followed by a booster vaccination in a subset of participants 13 months after the first immunisation. Vaccination was well tolerated and no vaccine-related serious adverse events were observed. VLA15 was immunogenic for all Borrelia serotypes. 11 months after the third vaccination, antibody titres returned almost to baseline. A subsequent booster vaccination elicited a strong anamnestic response, but antibody titres again dropped 6 months later, probably reaching the minimum protection titres established by the US Centers for Disease Control on the basis of experience with the LYMErix vaccine. Such a drop in titre represents a significant limitation inherent in all previous, current, and future Lyme disease vaccines based on the OspA antigen. Why is that?
What makes the OspA vaccine special is that it works while the tick is feeding (which takes several days) and attacks the pathogen only inside the tick, preventing its transmission. OspA is a dominant and essential membrane protein of B burgdorferi sensu lato spirochaetes while they are within the tick. However, the OspA protein is not present on the surface of the bacteria in the vertebrate host. This is confirmed by the observation that very few patients with early Lyme disease develop anti-OspA antibodies. Expression of OspA is downregulated just before spirochaetes transmission from the tick to the vertebrate host. Anti-OspA antibodies drained to the tick midgut during blood feeding on vaccinated humans bind to OspA and block transmission of B burgdorferi sensu lato to the vertebrate host. The exact mechanism of this complement-independent, antibody-mediated inhibition is not yet fully understood. However, the extent of B burgdorferi sensu lato inhibition inside the tick during its attachment correlates closely with the concentration of protective antibodies in the sera of immunised individuals. If the titre of anti-OspA antibodies is insufficient at the time of tick infestation, spirochaetes can escape, enter the host's skin, and most likely cause infection. Therefore, to maintain high titres of protective antibodies, annual boosters would be required before each tick season.
The results reported here by Bézay and colleagues encouraged the manufacturer to do further clinical trials. Valneva, in collaboration with Pfizer, completed two phase 2 clinical trials testing higher doses of VLA15 and an alternative vaccination schedule. These studies enrolled children older than 5 years and adults older than 65 years (groups of people who are statistically most likely to become infected), as well as individuals with a history of Lyme disease. Phase 3 clinical trials are currently underway in endemic areas of Europe and the USA. Valneva has received Fast Track designation from the US Food and Drug Administration for its vaccine and intends to submit a Biologics License Application in 2026. Overall, the VLA15 vaccine represents a milestone in our fight against Lyme disease and we eagerly await the results of the next clinical trials.
This Comment refers to: Bézay N. et al. 2023: Safety and immunogenicity of a novel multivalent OspA-based vaccine candidate against Lyme borreliosis: a randomised, phase 1 study in healthy adults. Lancet Infectious Diseases 23: (in press). DOI: 10.1016/S1473-3099(23)00210-4



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