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Complement enhances in vitro neutralizing potency of antibodies to human cytomegalovirus glycoprotein B (gB) and immune sera induced by gB/MF59 vaccination.

ABSTRACT: Human cytomegalovirus (HCMV) is the leading cause of in utero viral infection in the United States. Since congenital HCMV infection can lead to birth defects in newborns, developing a prophylactic vaccine is a high priority. One of the early experimental vaccines, composed of a recombinant glycoprotein B (gB) formulated with MF59 adjuvant, has demonstrated approximately 50% efficacy against HCMV infection in seronegative women. Using immune sera from two gB/MF59 Phase 1 studies in humans we showed that complement can enhance the in vitro HCMV neutralizing potency of antibodies induced by the gB/MF59 vaccination. To characterize this complement-dependent antiviral activity, we analyzed three rabbit non-neutralizing gB monoclonal antibodies (mAbs) with different biochemical profiles including epitope specificity. Two of the three mAbs, r272.7 and r210.4, exhibited neutralizing activity when complement was added to the assays, and this complement-dependent antiviral activity was not related to the antibody's affinity to gB but appeared to be associated with their epitope specificities. Moreover, neutralization could only be demonstrated when complement was present at or before viral entry, suggesting that IgG Fc-mediated function was not the basis for this antiviral activity. Lastly, we demonstrated that gB/MF59 immune sera contained antibodies that can cross-compete with r272.7 for gB binding and that the titers of these antibodies correlated with complement-dependent neutralization titers. These results suggested that gB antibodies with certain biochemical properties have neutralizing potency when complement is present and that this complement-dependent antiviral activity may be a part of immune components which conferred protection against HCMV infection by gB/MF59 vaccination.

SUBMITTER: Li F

PROVIDER: S-EPMC5730571 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Complement enhances in vitro neutralizing potency of antibodies to human cytomegalovirus glycoprotein B (gB) and immune sera induced by gB/MF59 vaccination.

Li Fengsheng F Freed Daniel C DC Tang Aimin A Rustandi Richard R RR Troutman Matthew C MC Espeseth Amy S AS Zhang Ningyan N An Zhiqiang Z McVoy Michael M Zhu Hua H Ha Sha S Wang Dai D Adler Stuart P SP Fu Tong-Ming TM

NPJ vaccines 20171214

Human cytomegalovirus (HCMV) is the leading cause of in utero viral infection in the United States. Since congenital HCMV infection can lead to birth defects in newborns, developing a prophylactic vaccine is a high priority. One of the early experimental vaccines, composed of a recombinant glycoprotein B (gB) formulated with MF59 adjuvant, has demonstrated approximately 50% efficacy against HCMV infection in seronegative women. Using immune sera from two gB/MF59 Phase 1 studies in humans we show ...[more]

PMID: 29263890

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Project description:Human cytomegalovirus (HCMV) is an important, ubiquitous pathogen that causes severe clinical disease in immunocompromised individuals, such as organ transplant recipients and infants infected in utero. Antiviral chemotherapy remains problematic due to toxicity of the available compounds and the emergence of viruses resistant to available antiviral therapies. Antiviral antibodies could represent a valuable alternative strategy to limit the clinical consequences of viral disease in patients. The envelope glycoprotein B (gB) of HCMV is a major antigen for the induction of virus neutralizing antibodies. However, the role of anti-gB antibodies in the course of the infection in-vivo remains unknown. We have used a murine CMV (MCMV) model to generate and study a number of anti-gB monoclonal antibodies (mAbs) with differing virus-neutralizing capacities. The mAbs were found to bind to similar antigenic structures on MCMV gB that are represented in HCMV gB. When mAbs were used in immunodeficient RAG-/- hosts to limit an ongoing infection we observed a reduction in viral load both with mAbs having potent neutralizing capacity in-vitro as well as mAbs classified as non-neutralizing. In a therapeutic setting, neutralizing mAbs showed a greater capacity to reduce the viral burden compared to non-neutralizing antibodies. Efficacy was correlated with sustained concentration of virus neutralizing mAbs in-vivo rather than their in-vitro neutralizing capacity. Combinations of neutralizing mAbs further augmented the antiviral effect and were found to be as potent in protection as polyvalent serum from immune animals. Prophylactic administration of mAbs before infection was also protective and both neutralizing and non-neutralizing mAbs were equally effective in preventing lethal infection of immunodeficient mice. In summary, our data argue that therapeutic application of potently neutralizing mAbs against gB represent a strategy to modify the outcome of CMV infection in immunodeficient hosts. When present before infection, both neutralizing and non-neutralizing anti-gB exhibited protective capacity.

Project description:A vaccine to prevent maternal acquisition of human cytomegalovirus (HCMV) during pregnancy is a primary strategy to reduce the incidence of congenital disease. The MF59-adjuvanted glycoprotein B (gB) protein subunit vaccine (gB/MF59) is the most efficacious vaccine tested to date for this indication. We previously identified that gB/MF59 vaccination elicited poor neutralizing antibody responses and an immunodominant response against gB antigenic domain 3 (AD-3). Thus, we sought to test novel gB vaccines to improve functional antibody responses and reduce AD-3 immunodominance. Groups of juvenile New Zealand White rabbits were administered 3 sequential doses of the full-length gB protein with an MF59-like squalene-based adjuvant, the gB ectodomain protein (lacking AD-3) with squalene adjuvant, or lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA encoding full-length gB. All vaccines were highly immunogenic with similar kinetics and comparable peak gB-binding and functional antibody responses. The AD-3-immunodominant IgG response following human gB/MF59 vaccination was closely mimicked in rabbits. Though gB ectodomain subunit vaccination eliminated targeting of epitopes in AD-3, it did not improve vaccine-elicited neutralizing or nonneutralizing antibody functions. gB nucleoside-modified mRNA-LNP-immunized rabbits exhibited an enhanced durability of vaccine-elicited antibody responses. Furthermore, the gB mRNA-LNP vaccine enhanced the breadth of IgG binding responses against discrete gB peptides. Finally, low-magnitude gB-specific T cell activity was observed in the full-length gB protein and mRNA-LNP groups, though not in ectodomain-vaccinated rabbits. Altogether, these data suggest that the use of gB nucleoside-modified mRNA-LNP vaccines is a viable strategy for improving on the partial efficacy of gB/MF59 vaccination and should be further evaluated in preclinical models.IMPORTANCE Human cytomegalovirus (HCMV) is the most common infectious cause of infant birth defects, resulting in permanent neurological disability for one newborn child every hour in the United States. After more than a half century of research and development, we remain without a clinically licensed vaccine or immunotherapeutic to reduce the burden of HCMV-associated disease. In this study, we sought to improve upon the glycoprotein B protein vaccine (gB/MF59), the most efficacious HCMV vaccine evaluated in a clinical trial, via targeted modifications to either the protein structure or vaccine formulation. Utilization of a novel vaccine platform, nucleoside-modified mRNA formulated in lipid nanoparticles, increased the durability and breadth of vaccine-elicited antibody responses. We propose that an mRNA-based gB vaccine may ultimately prove more efficacious than the gB/MF59 vaccine and should be further evaluated for its ability to elicit antiviral immune factors that can prevent HCMV-associated disease.

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve in humans. Spike protein mutations increase transmission and potentially evade antibodies raised against the original sequence used in current vaccines. Our evaluation of serum neutralizing activity in both persons soon after SARS-CoV-2 infection (in April 2020 or earlier) or vaccination without prior infection confirmed that common spike mutations can reduce antibody antiviral activity. However, when the persons with prior infection were subsequently vaccinated, their antibodies attained an apparent biologic ceiling of neutralizing potency against all tested variants, equivalent to the original spike sequence. These findings indicate that additional antigenic exposure further improves antibody efficacy against variants. IMPORTANCE As SARS-CoV-2 evolves to become better suited for circulating in humans, mutations have occurred in the spike protein it uses for attaching to cells it infects. Protective antibodies from prior infection or vaccination target the spike protein to interfere with its function. These mutations can reduce the efficacy of antibodies generated against the original spike sequence, raising concerns for reinfections and vaccine failures, because current vaccines contain the original sequence. In this study, we tested antibodies from people infected early in the pandemic (before spike variants started circulating) or people who were vaccinated without prior infection. We confirmed that some mutations reduce the ability of antibodies to neutralize the spike protein, whether the antibodies were from past infection or vaccination. Upon retesting the previously infected persons after vaccination, their antibodies gained the same ability to neutralize mutated spike as the original spike, suggesting that the combination of infection and vaccination drove the production of enhanced antibodies to reach a maximal level of potency. Whether this can be accomplished by vaccination alone remains to be determined, but the results suggest that booster vaccinations may help improve efficacy against spike variants through improving not only antibody quantity, but also quality.

Dataset Information

Complement enhances in vitro neutralizing potency of antibodies to human cytomegalovirus glycoprotein B (gB) and immune sera induced by gB/MF59 vaccination.

Publications

Complement enhances in vitro neutralizing potency of antibodies to human cytomegalovirus glycoprotein B (gB) and immune sera induced by gB/MF59 vaccination.

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