Agglutination of Borreliella burgdorferi by Transmission-Blocking OspA Monoclonal Antibodies and Monovalent Fab Fragments

Frye, Amber M.; Ejemel, Monir; Cavacini, Lisa A.; Wang, Yan; Rudolph, M.; Song, Renjie; Mantis, Nicholas J.

doi:10.1128/iai.00306-22

Cited by 6 publications

(20 citation statements)

References 62 publications

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“…MAbs LA-2, 319-44, and 857-2 were recently shown to promote B. burgdorferi agglutination in vitro, possibly reflecting a biological activity of anti-OspA antibodies that entraps spirochetes within the tick vector and prevents transmission to human hosts . Thus, the B cell epitope map presented here likely encompasses important functional targets on OspA that contribute to immunity to LD.…”

Section: Resultsmentioning

confidence: 99%

“…burgdorferi immune serum, not MAbs, so it remains unclear whether the observed mode of complement activation is specific to certain antigen targets such as OspA. Certainly, further investigation into 319-28 and 212-55’s borreliacidal activities is warranted, as is a more in-depth analysis of cooperativity among MAbs of different epitope specificities in conferring borreliacidal and agglutination activities …”

Section: Resultsmentioning

confidence: 99%

“…Certainly, further investigation into 319-28 and 212-55's borreliacidal activities is warranted, as is a more in-depth analysis of cooperativity among MAbs of different epitope specificities in conferring borreliacidal and agglutination activities. 58 ■ MATERIALS AND METHODS OspA Human MAbs and Recombinant OspA. OspA MAbs listed in Table 1 were expressed and purified as described.…”

mentioning

confidence: 99%

“…33 MAbs LA-2, 319-44, and 857-2 were recently shown to promote B. burgdorferi agglutination in vitro, possibly reflecting a biological activity of anti-OspA antibodies that entraps spirochetes within the tick vector and prevents transmission to human hosts. 58 Thus, the B cell epitope map presented here likely encompasses important functional targets on OspA that contribute to immunity to LD. The composite B cell epitope map of OspA generated herein (Figure 7) should prove useful in the design and serological interpretation of next-generation LD vaccines, even with the caveat that our investigation was restricted to a single OspA serotype derived from B. burgdorferi sensu stricto, the genospecies most represented in North America.…”

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confidence: 99%

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Human B Cell Epitope Map of the Lyme Disease Vaccine Antigen, OspA

Haque

Ejemel²,

Vance

et al. 2022

ACS Infect. Dis.

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The Lyme disease (LD) vaccine formerly approved for use in the United States consisted of recombinant outer surface protein A (OspA) from Borrelia burgdorferi sensu stricto (ss), the bacterial genospecies responsible for the vast majority of LD in North America. OspA is an ∼30 kDa lipoprotein made up of 21 antiparallel β-strands and a C-terminal α-helix. In clinical trials, protection against LD following vaccination correlated with serum antibody titers against a single epitope near the C-terminus of OspA, as defined by the mouse monoclonal antibody (MAb), LA-2. However, the breadth of the human antibody response to OspA following vaccination remains undefined even as next-generation multivalent OspA-based vaccines are under development. In this report, we employed hydrogen exchange–mass spectrometry (HX-MS) to localize the epitopes recognized by a unique panel of OspA human MAbs, including four shown to passively protect mice against experimental B. burgdorferi infection and one isolated from a patient with antibiotic refractory Lyme arthritis. The epitopes grouped into three spatially distinct bins that, together, encompass more than half the surface-exposed area of OspA. The bins corresponded to OspA β-strands 8–10 (bin 1), 11–13 (bin 2), and 16–20 plus the C-terminal α-helix (bin 3). Bin 3 was further divided into sub-bins relative to LA-2’s epitope. MAbs with complement-dependent borreliacidal activity, as well as B. burgdorferi transmission-blocking activity in the mouse model were found within each bin. Therefore, the resulting B cell epitope map encompasses functionally important targets on OspA that likely contribute to immunity to B. burgdorferi.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Human B Cell Epitope Map of the Lyme Disease Vaccine Antigen, OspA

Haque

Ejemel²,

Vance

et al. 2022

ACS Infect. Dis.

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“…Assays were essentially done as described 17 . B. burgdorferi strain B31, cultured in BSK‐II media lacking gelatin, was grown at 33°C with 5% CO 2 to mid‐log phase, then diluted 1/10 in medium and grown at 23°C to early‐log phase to promote OspA expression and suppress mammalian host‐associated gene expression.…”

Section: Methodsmentioning

confidence: 99%

Structure of a transmission blocking antibody in complex with Outer surface protein A from the Lyme disease spirochete, Borreliella burgdorferi

et al. 2023

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Abstract319‐44 is a human monoclonal antibody capable of passively protecting mice against tick‐mediated infection with Borreliella burgdorferi, the bacterial genospecies responsible for Lyme disease in North America. In vitro, 319‐44 has complement‐dependent borreliacidal activity and spirochete agglutinating properties. Here, we report the 2.2 Å‐resolution crystal structure of 319‐44 Fab fragments in complex with Outer surface protein A (OspA), the ~30 kDa lipoprotein that was the basis of the first‐generation Lyme disease vaccine approved in the United States. The 319‐44 epitope is focused on OspA β‐strands 19, 20, and 21, and the loops between β‐strands 16‐17, 18‐19, and 20‐21. Contact with loop 20‐21 explains competition with LA‐2, the murine monoclonal antibody used to estimate serum borreliacidal activities in the first‐generation Lyme disease vaccine clinical trials. A high‐resolution B‐cell epitope map of OspA will accelerate structure‐based design of second generation OspA‐based vaccines.

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Preclinical Evidence for the Protective Capacity of Antibodies Induced by Lyme Vaccine Candidate VLA15 in People

Lundberg,

Hochreiter,

Timofoyeva

et al. 2024

Open Forum Infectious Diseases

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Background Vaccine candidate VLA15 is designed to protect against the dominant Borrelia genospecies-causing Lyme disease in North America and Europe. Active immunization with VLA15 has protected in the mouse model of tick challenge. VLA15 is currently under evaluation in clinical studies for the prevention of Lyme borreliosis. Methods Mice were passively administered sera from clinical trial participants vaccinated with VLA15, or normal human serum from unvaccinated individuals as control. Post-transfer serum anti-OspA IgG titers were assessed by ELISA. Following passive transfer, mice were challenged with Ixodes ticks colonized with Borrelia burgdorferi (OspA serotype 1) or Borrelia afzelii (OspA serotype 2) and infection was determined by serology for VlsE C6 or by PCR and culture to assess the presence of Borrelia bacteria. Results Passive transfer of immune sera prevented transmission of Borrelia from the tick vector and protected mice against challenge. Post-transfer protective threshold IgG antibody titers were observed in this animal model of 131 U/mL for B. burgdorferi (OspA serotype 1) and 352 U/mL for B. afzelii (serotype 2). Conclusions Passive transfer of sera from trial participants immunized with VLA15 protected mice from borreliosis in a tick challenge model. This indicates that VLA15 induces functional immune responses in people that can be linked to efficacy in a stringent preclinical model.

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Agglutination of Borreliella burgdorferi by Transmission-Blocking OspA Monoclonal Antibodies and Monovalent Fab Fragments

Cited by 6 publications

References 62 publications

Human B Cell Epitope Map of the Lyme Disease Vaccine Antigen, OspA

Human B Cell Epitope Map of the Lyme Disease Vaccine Antigen, OspA

Structure of a transmission blocking antibody in complex with Outer surface protein A from the Lyme disease spirochete, Borreliella burgdorferi

Preclinical Evidence for the Protective Capacity of Antibodies Induced by Lyme Vaccine Candidate VLA15 in People

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