Academic journal article Canadian Journal of Public Health

A Systematic Review and Meta-Analysis for the Adverse Effects, Immunogenicity and Efficacy of Lyme Disease Vaccines: Guiding Novel Vaccine Development

Academic journal article Canadian Journal of Public Health

A Systematic Review and Meta-Analysis for the Adverse Effects, Immunogenicity and Efficacy of Lyme Disease Vaccines: Guiding Novel Vaccine Development

Article excerpt

Lyme disease or Lyme borreliosis (LB) is the most prevalent arthropod-borne disease in North America.1 It is caused by Borrelia burgdorferi sensu stricto (B. burgdorferi) in North America, which is transmitted by Ixodes scapularis and Ixodes pacificus blacklegged ticks.2 Currently, LB is becoming a major health problem in Canada due to northward expansion of the tick population driven by introduction of B. burgdorferi and its vectors by migratory birds,2 and facilitated by a warming climate which shortens ticks' lifecycles and increases the species' survival.3,4 The expanding geographical distribution of ticks has been associated with an approximately sixfold increase in LB incidence (from 128 to 707 cases) from 2009 to 2015.5 The true number of cases is expected, however, to be higher, as it is unlikely that all cases are captured by surveillance. As of 2014, LB was endemic in 22 locations across New Brunswick, Nova Scotia, Quebec, Ontario and Manitoba, in comparison to only one location in Ontario in the 1970s.6

The expansion of tick populations and the subsequent increased incidence of LB cases underscore the demand for developing effective and safe approaches for disease prevention and control.

Currently, however, there is no human vaccine available.7 Two recombinant monovalent vaccines were simultaneously developed by SmithKline Beecham (LYMErix) and Pasteur Merieux Connaught (ImmuLyme) in the 1990s. Both were based on outer surface protein A (OspA) lipoprotein expressed in E. coli, adsorbed to aluminum hydroxide in phosphate-buffered saline.8-10 The purpose was to develop circulating bactericidal antibodies against B. burgdorferi that would be sufficient to prevent the bacterial transmission from the tick gut to the host following a tick bite.11 Both vaccines underwent large Phase III clinical trials with over 10 000 subjects each and produced promising outcomes.8,9 Both ImmuLyme and LYMErix exhibited moderate efficacy (49%-68%) in the first year with high efficacy (83%-92%) following a booster dose.8,9 However, FDA approval in 1998 was sought only for LYMErix.8,12

Following the introduction of LYMErix, it was suspected that molecular mimicry between the human lymphocyte functionassociated antigen-1 (hLFA-1) adhesion molecules and B. burgdorferiOspA was contributing to the development of antibody-mediated arthritogenesis.13 The sequence similarities between OspA and hLFA-1, particularly in patients with HLA-DR4, was thought to be the underlying mechanism of progression to the persistent form of LB observed in a small percent of patients.13-15 Indeed, HLA-DR4 and HLA-DR2 alleles were previously linked to chronic Lyme arthritis in LB cases.16 This led to questioning the safety of using LYMErix in patients with HLA-DR4 allele being based on OspA antigen. Further investigation led to two reports suggesting the development of chronic arthritis in a hamster model and four human cases.17,18 These indications - although not corroborated against the safety of LYMErix by the FDA - together with its slow acceptance due to high cost, the extensive anti-vaccination campaigns, the complicated administration schedules and the failure to identify populations at risk of infection, all resulted in its voluntary withdrawal from the market in 2002 together with its licence.7-11

More recently, Baxter BioScience developed a second-generation multivalent vaccine against LB with a purpose of global application.7,19 Although B. burgdorferi sensu stricto causes Lyme disease in North America, several other pathogenic strains are found across Europe and worldwide. The new trial-vaccine, therefore, was comprised of three chimeric OspA protective epitopes of B. burgdorferi, B. afzelii, B. garinii and B. bavariensis which are intended to prevent the possibility of molecular mimicry and induce potent antibody responses against all major Borrelia species.19 Safety and immunogenicity evaluation of that vaccine were recently conducted through Phase I/II dose-finding studies in adult populations. …

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