Preexisting antibodies can protect against congenital cytomegalovirus infection in monkeys

Nelson, Cody S.; Cruz, Diana Vera; Tran, Dollnovan; Bialas, Kristy M.; Stamper, Lisa; Wu, Huali; Gilbert, Margaret H.; Blair, Robert V; Álvarez, Xavier; Itell, Hannah L.; Chen, Meng; Deshpande, Ashlesha; Chiuppesi, Flavia; Wussow, Felix; Diamond, Don J.; Vandergrift, Nathan; Walter, Mark R.; Barry, Peter A.; Cohen‐Wolkowiez, Michael; Koelle, Katia; Kaur, Amitinder; Permar, Sallie R.

doi:10.1172/jci.insight.94002

Cited by 64 publications

(116 citation statements)

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“…Virus-neutralizing antibodies targeting the immunodominant CMV glycoprotein B (gB), as well as the glycoprotein H/L (gH/gL) complex, have been shown to prevent CMV transmission in a guinea pig CMV (GPCMV) congenital infection model (34)(35)(36)(37). Moreover, passively administered polyclonal anti-CMV IgG, even in the absence of T cell responses, demonstrated protective capacity in a rhesus macaque CMV (RhCMV) model of congenital infection (38). In addition, antibodies against another CMV glycoprotein complex involved in epithelial and endothelial cell entry of virusthe "pentameric complex" (PC) of glycoproteins gH/gL/UL128/130/131-have been shown to cross-neutralize diverse clinical isolates of CMV (39), an important observation in light of the role that recurrent infection (due, at least in some cases, to reinfection with a new strain in a previously "immune" woman) plays in congenital CMV transmission.…”

Section: Correlates Of Protective Maternal Immunity and Potential Formentioning

confidence: 99%

“…Challenge studies have shown that large doses of CMV can overcome prior immunity that would otherwise protect against lower doses of virus (44). Moreover, the rapidity with which containment of CMV replication and systemic viremia occurs after primary infection may play an important role in predicting placental transmission (38). Although CMV is described as a slowly replicating virus in cell culture, analysis of the dynamics of replication in vivo suggests that the doubling time of the virus is actually much shorter, on the order of 1 day in immunocompromised patients (45).…”

Section: Correlates Of Protective Maternal Immunity and Potential Formentioning

confidence: 99%

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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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Section: Correlates Of Protective Maternal Immunity and Potential Formentioning

confidence: 99%

Section: Correlates Of Protective Maternal Immunity and Potential Formentioning

confidence: 99%

Progress toward Development of a Vaccine against Congenital Cytomegalovirus Infection

Schleiss

Permar

Plotkin

2017

Clin Vaccine Immunol

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“…In this study we were able to epitope-map and define the function of antibodies elicited by these three experimental vaccines, then compare to previously-reported immune correlates of protection (Nelson, Journal of Infectious Diseases , 2019, in press). HCMV-neutralizing IgG has previously been associated with reduced viral systemic dissemination [20, 28, 29]. Specifically, antibodies targeting gB AD-2 are correlated with reduced incidence of viremia and congenital disease [19, 20], though AD-2-specific antibodies were not elicited to any appreciable extent by the vaccines tested in this investigation ( Figure 4H ).…”

Section: Discussionmentioning

confidence: 62%

HCMV glycoprotein B nucleoside-modified mRNA vaccine elicits antibody responses with greater durability and breadth than MF59-adjuvanted gB protein immunization

Nelson

Jenks

Pardi

et al. 2019

Preprint

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2 3 4 HCMV glycoprotein B nucleoside-modified mRNA vaccine elicits antibody responses with 5 greater durability and breadth than MF59-adjuvanted gB protein immunization 6 7 Short Title: Immunogenicity of next-generation HCMV gB vaccines 8 9 Cody 22 23 Abstract WC: 300 (300 max) 24 Author summary WC: 188 (200 max) 25 Main Text WC: 3,177 26 Methods WC: 3,142 2 27 Abstract:28 A vaccine to prevent maternal acquisition of human cytomegalovirus (HCMV) during pregnancy 29 is a primary strategy to reduce the incidence of congenital disease. Similarly, vaccination of 30 transplant recipients against HCMV has been proposed to prevent transplant-associated HCMV 31 morbidity. The MF59-adjuvanted glycoprotein B protein subunit vaccine (gB/MF59) is the most 32 efficacious tested to-date for both indications. We previously identified that gB/MF59 vaccination 33 elicited poor neutralizing antibody responses and an immunodominant response against gB 34 antigenic domain 3 (AD-3). Thus, we sought to test novel gB vaccines to improve functional 35 antibody responses and reduce AD-3 immunodominance. Groups of juvenile New Zealand White 36 rabbits were administered 3 sequential doses of full-length gB protein with an MF59-like squalene 37 adjuvant (analogous to clinically-tested vaccine), gB ectodomain protein (lacking AD-3) with 38 squalene adjuvant, or lipid nanoparticle (LNP)-packaged nucleoside-modified mRNA encoding 39 full-length gB. The AD-3 immunodominant IgG response following human gB/MF59 vaccination 40 was closely mimicked in rabbits, with 78% of binding antibodies directed against this region in the 41 full-length gB protein group compared to 1% and 46% in the ectodomain and mRNA-LNP-42 vaccinated groups, respectively. All vaccines were highly immunogenic with similar kinetics and 43 comparable peak gB-binding and functional antibody responses. Although gB ectodomain subunit 44 vaccination reduced targeting of non-neutralizing epitope AD-3, it did not improve vaccine-elicited 45 neutralizing or non-neutralizing antibody functions. gB nucleoside-modified mRNA-LNP-46 immunized rabbits exhibited enhanced durability of IgG binding to soluble and cell membrane-47 associated gB protein as well as HCMV-neutralizing function. Furthermore, the gB mRNA-LNP 48 vaccine enhanced breadth of IgG binding responses against discrete gB peptide residues. Finally, 49 low-magnitude gB-specific T cell activity was observed in the full-length gB protein and mRNA-50 LNP vaccine groups, though not in ectodomain-vaccinated rabbits. Altogether, these data suggest 51 that the gB mRNA-LNP vaccine candidate, aiming to improve upon the partial efficacy of gB/MF59 52 vaccination, should be further evaluated in preclinical models. Author summary:54 Human cytomegalovirus (HCMV) is the most common infectious cause of infant birth defects, 55 resulting in permanent neurologic disability for one newborn child every hour in the United States.56 Furthermore, this virus causes significant morbidity and mortality in immune-suppressed 57 transplant recipients. Af...

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“…Recent studies show that maternal antibodies can transfer into the developing peripheral and central nervous system during gestation [11,18]. These findings coupled with reports that maternal antibodies are effective against congenital Zika [19] and cytomegalovirus [20] infections suggest a broader applicability of maternal immunizations to other TORCH pathogens.…”

mentioning

confidence: 88%

Preventing Neonatal Herpes Infections Through Maternal Immunization

Jiang

Leib

2017

Future Virol.

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Preexisting antibodies can protect against congenital cytomegalovirus infection in monkeys

Cited by 64 publications

References 70 publications

Progress toward Development of a Vaccine against Congenital Cytomegalovirus Infection

Progress toward Development of a Vaccine against Congenital Cytomegalovirus Infection

HCMV glycoprotein B nucleoside-modified mRNA vaccine elicits antibody responses with greater durability and breadth than MF59-adjuvanted gB protein immunization

Preventing Neonatal Herpes Infections Through Maternal Immunization

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