Replication-defective lymphocytic choriomeningitis virus vectors expressing guinea pig cytomegalovirus gB and pp65 homologs are protective against congenital guinea pig cytomegalovirus infection

Cardin, Rhonda D.; Bravo, Fernando; Pullum, Derek A.; Orlinger, Klaus K.; Watson, Elizabeth M.; Aspoeck, Andreas; Fuhrmann, G; Guirakhoo, Farshad; Monath, Thomas P.; Bernstein, David I.

doi:10.1016/j.vaccine.2016.03.005

Cited by 27 publications

(26 citation statements)

References 34 publications

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“…In contrast to a previous report by Cardin (37), the current study demonstrated that gB-containing LCMV vaccines were superior to GPpp65 LCMV vaccines in protecting against pup mortality and in reducing pup viral load. Cardin et al observed 23% pup mortality in the GPgB-vaccinated group and 26% in the pp65-vaccinated group, compared to 49% mortality in control pups (37).…”

Section: Figcontrasting

confidence: 99%

Additive Protection against Congenital Cytomegalovirus Conferred by Combined Glycoprotein B/pp65 Vaccination Using a Lymphocytic Choriomeningitis Virus Vector

Schleiss

Berka²,

Watson³

et al. 2017

Clin Vaccine Immunol

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Subunit vaccines for prevention of congenital cytomegalovirus (CMV) infection based on glycoprotein B (gB) and pp65 are in clinical trials, but it is unclear whether simultaneous vaccination with both antigens enhances protection. We undertook evaluation of a novel bivalent vaccine based on nonreplicating lymphocytic choriomeningitis virus (rLCMV) vectors expressing a cytoplasmic tail-deleted gB [gB(dCt)] and full-length pp65 from human CMV in mice. Immunization with the gB(dCt) vector alone elicited a comparable gB-binding antibody response and a superior neutralizing response to that elicited by adjuvanted subunit gB. Immunization with the pp65 vector alone elicited robust T cell responses. Comparable immunogenicity of the combined gB(dCt) and pp65 vectors with the individual monovalent formulations was demonstrated. To demonstrate proof of principle for a bivalent rLCMV-based HCMV vaccine, the congenital guinea pig cytomegalovirus (GPCMV) infection model was used to compare rLCMV vectors encoding homologs of pp65 (GP83) and gB(dCt), alone and in combination versus Freund's adjuvanted recombinant gB. Both vectors elicited significant immune responses, and no loss of gB immunogenicity was noted with the bivalent formulation. Combined vaccination with rLCMV-vectored GPCMV gB(dCt) and pp65 (GP83) conferred better protection against maternal viremia than subunit or either monovalent rLCMV vaccine. The bivalent vaccine also was significantly more effective in reducing pup mortality than the monovalent vaccines. In summary, bivalent vaccines with rLCMV vectors expressing gB and pp65 elicited potent humoral and cellular responses and conferred protection in the GPCMV model. Further clinical trials of LCMV-vectored HCMV vaccines are warranted.

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Section: Figcontrasting

confidence: 99%

Additive Protection against Congenital Cytomegalovirus Conferred by Combined Glycoprotein B/pp65 Vaccination Using a Lymphocytic Choriomeningitis Virus Vector

Schleiss

Berka²,

Watson³

et al. 2017

Clin Vaccine Immunol

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“…Analysis of viral loads in pup tissues from both groups demonstrated that the tissues from the control nonvaccinated group had a higher frequency of GPCMV-positive tissue (Table 3). A 52.4% reduction in GPCMV transmission in the vaccinated group (23.5% transmission) compared to the control group (75.9% transmission) indicated that the DISC vaccine strategy was more effective than levels reported for studies with live GPCMV vaccine strains (78,80) or gB-based vaccine strategies (76,77,79,82). A comparison of the outcome of our study versus those of previous GPCMV vaccine studies is covered in more detail in the Discussion.…”

Section: Fig 11mentioning

confidence: 66%

“…Consequently, a large amount of the gB immune response was potentially directed to the linear, homologous AD-1 domain (92) rather than other gB antigen targets. However, a more recent study by Cardin et al (82), which used a recombinant lymphocytic choriomeningitis virus vector that encoded gB with a C-terminal domain but lacked a transmembrane domain, did not increase protection against transmission (reduced from 83% to 60%) despite generation of high titers of antibody to gB.…”

Section: Discussionmentioning

confidence: 96%

A Novel Non-Replication-Competent Cytomegalovirus Capsid Mutant Vaccine Strategy Is Effective in Reducing Congenital Infection

Choi

Root

McGregor

2016

J Virol

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Congenital cytomegalovirus (CMV) infection is a leading cause of mental retardation and deafness in newborns. The guinea pig is the only small animal model for congenital CMV infection. A novel CMV vaccine was investigated as an intervention strategy against congenital guinea pig cytomegalovirus (GPCMV) infection. In this disabled infectious single-cycle (DISC) vaccine strategy, a GPCMV mutant virus was used that lacked the ability to express an essential capsid gene (the UL85 homolog GP85) except when grown on a complementing cell line. In vaccinated animals, the GP85 mutant virus (GP85 DISC) induced an antibody response to important glycoprotein complexes considered neutralizing target antigens (gB, gH/gL/gO, and gM/gN). The vaccine also generated a T cell response to the pp65 homolog (GP83), determined via a newly established guinea pig gamma interferon enzyme-linked immunosorbent spot assay. In a congenital infection protection study, GP85 DISC-vaccinated animals and a nonvaccinated control group were challenged during pregnancy with wild-type GPCMV (10 5 PFU). The pregnant animals carried the pups to term, and viral loads in target organs of pups were analyzed. Based on live pup births in the vaccinated and control groups (94.1% versus 63.6%), the vaccine was successful in reducing mortality (P ‫؍‬ 0.0002). Additionally, pups from the vaccinated group had reduced CMV transmission, with 23.5% infected target organs versus 75.9% in the control group. Overall, these preliminary studies indicate that a DISC CMV vaccine strategy has the ability to induce an immune response similar to that of natural virus infection but has the increased safety of a non-replication-competent virus, which makes this approach attractive as a CMV vaccine strategy. IMPORTANCECongenital CMV infection is a leading cause of mental retardation and deafness in newborns. An effective vaccine against CMV remains an elusive goal despite over 50 years of CMV research. The guinea pig, with a placenta structure similar to that in humans, is the only small animal model for congenital CMV infection and recapitulates disease symptoms (e.g., deafness) in newborn pups. In this report, a novel vaccine strategy against congenital guinea pig cytomegalovirus (GPCMV) infection was developed, characterized, and tested for efficacy. This disabled infectious single-cycle (DISC) vaccine strategy induced a neutralizing antibody or a T cell response to important target antigens. In a congenital infection protection study, animals were protected against CMV in comparison to the nonvaccinated group (52% reduction of transmission). This novel vaccine was more effective than previously tested gB-based vaccines and most other strategies involving live virus vaccines. Overall, the DISC vaccine is a safe and promising approach against congenital CMV infection. H uman cytomegalovirus (HCMV), a betaherpesvirus, has evolved very closely with its human host. Virus infection in a healthy host is normally asymptomatic but leads to a lifelong infection. In contrast,...

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“…This feature might be highly desirable for sustaining protection (conferred by periodic booster immunizations) against congenital CMV in women of reproductive age during serial pregnancies. The utility of this approach was recently demonstrated in the GPCMV model of congenital infection (63,64), providing support for evaluation of these vectors in human clinical trials. This platform was developed by Hookipa Biotech AG.…”

Section: Vectored CMV Vaccinesmentioning

confidence: 91%

Progress toward Development of a Vaccine against Congenital Cytomegalovirus Infection

Schleiss

Permar

Plotkin

2017

Clin Vaccine Immunol

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A vaccine against congenital human cytomegalovirus (CMV) infection is a major public health priority. Congenital CMV causes substantial long-term morbidity, particularly sensorineural hearing loss (SNHL), in newborns, and the public health impact of this infection on maternal and child health is underrecognized. Although progress toward development of a vaccine has been limited by an incomplete understanding of the correlates of protective immunity for the fetus, knowledge about some of the key components of the maternal immune response necessary for preventing transplacental transmission is accumulating. Moreover, although there have been concerns raised about observations indicating that maternal seropositivity does not fully prevent recurrent maternal CMV infections during pregnancy, it is becoming increasing clear that preconception immunity does confer some measure of protection against both CMV transmission and CMV disease (if transmission occurs) in the newborn infant. Although the immunity to CMV conferred by both infection and vaccination is imperfect, there are encouraging data emerging from clinical trials demonstrating the immunogenicity and potential efficacy of candidate CMV vaccines. In the face of the knowledge that between 20,000 and 30,000 infants are born with congenital CMV in the United States every year, there is an urgent and compelling need to accelerate the pace of vaccine trials. In this minireview, we summarize the status of CMV vaccines in clinical trials and provide a perspective on what would be required for a CMV immunization program to become incorporated into clinical practice.

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Replication-defective lymphocytic choriomeningitis virus vectors expressing guinea pig cytomegalovirus gB and pp65 homologs are protective against congenital guinea pig cytomegalovirus infection

Cited by 27 publications

References 34 publications

Additive Protection against Congenital Cytomegalovirus Conferred by Combined Glycoprotein B/pp65 Vaccination Using a Lymphocytic Choriomeningitis Virus Vector

Additive Protection against Congenital Cytomegalovirus Conferred by Combined Glycoprotein B/pp65 Vaccination Using a Lymphocytic Choriomeningitis Virus Vector

A Novel Non-Replication-Competent Cytomegalovirus Capsid Mutant Vaccine Strategy Is Effective in Reducing Congenital Infection

Progress toward Development of a Vaccine against Congenital Cytomegalovirus Infection

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