Functionally inactivated dominant viral antigens of human cytomegalovirus delivered in replication incompetent adenovirus type 6 vectors as vaccine candidates.

T cell immunity is critical in controlling human cytomegalovirus (HCMV) infection in transplant recipients, and T cells targeting viral immediate early proteins such as IE1, IE2 and pp65 have been speculated to be more effective against reactivation. Here we report efforts to construct replication incompetent adenovirus 6 vectors expressing these viral antigens as vaccine candidates. To reduce the potential liabilities of these viral proteins as vaccine antigens, we introduced mutations to inactivate their reported functions including their nuclear localization signals. The modifications greatly reduced their localization to the nuclei, thus limiting their interactions with cellular proteins important for cell cycle modulation and transactivation. The immunogenicity of modified pp65, IE1 and IE2 vaccines was comparable to their wild-type counterparts in mice and the immunogenicity of the modified antigens was demonstrated in non-human primates.

Peptide vaccination in the presence of adjuvants in patients after hematopoietic stem cell transplantation with CD4+ T cell reconstitution elicits consistent CD8+ T cell responses.

Rationale: Patients receiving an allogeneic stem cell graft from cytomegalovirus (CMV) seronegative donors are particularly prone to CMV reactivation with a high risk of disease and mortality. Therefore we developed and manufactured a novel vaccine and initiated a clinical phase I trial with a CMV phosphoprotein 65 (CMVpp65)-derived peptide. Methods: Ten patients after allogeneic stem cell transplantation received four vaccinations at a biweekly interval. All patients were monitored for CMVpp65 antigenemia. Flow cytometry for CMV-specific CD8+ and γδ T cells as well as neutralizing anti-CMV antibodies were correlated to clinical parameters. Results: The vaccination was well tolerated. Seven of nine patients cleared CMVpp65 antigenemia after four vaccinations and are still free from antigenemia to this day. Two patients with CMV reactivation showed persisting CMV antigenemia. One patient received prophylactic vaccination and did not develop antigenemia. An increase of up to six-fold in frequency of both CMV-specific CD8+ T cells and/or Vδ2negative γδ T cells was detected. Titers of neutralizing antibodies increased up to the tenfold. Humoral and cellular immune responses correlated with clearance of CMV. Conclusion: In summary, CMVpp65 peptide vaccination for patients after allogeneic stem cell transplantation at high risk for CMV reactivation was safe, well tolerated and clinically encouraging. A study in solid-organ transplant patients is ongoing.

MVA vaccine encoding CMV antigens safely induces durable expansion of CMV-specific T cells in healthy adults.

Attenuated poxvirus modified vaccinia Ankara (MVA) is a useful viral-based vaccine for clinical investigation, because of its excellent safety profile and property of inducing potent immune responses against recombinant (r) antigens. We developed Triplex by constructing an rMVA encoding 3 immunodominant cytomegalovirus (CMV) antigens, which stimulates a host antiviral response: UL83 (pp65), UL123 (IE1-exon4), and UL122 (IE2-exon5). We completed the first clinical evaluation of the Triplex vaccine in 24 healthy adults, with or without immunity to CMV and vaccinia virus (previous DryVax smallpox vaccination). Three escalating dose levels (DL) were administered IM in 8 subjects/DL, with an identical booster injection 28 days later and 1-year follow-up. Vaccinations at all DL were safe with no dose-limiting toxicities. No vaccine-related serious adverse events were documented. Local and systemic reactogenicity was transient and self-limiting. Robust, functional, and durable Triplex-driven expansions of CMV-specific T cells were detected by measuring T-cell surface levels of 4-1BB (CD137), binding to CMV-specific HLA multimers, and interferon-γ production. Marked and durable CMV-specific T-cell responses were also detected in Triplex-vaccinated CMV-seronegatives, and in DryVax-vaccinated subjects. Long-lived memory effector phenotype, associated with viral control during CMV primary infection, was predominantly found on the membrane of CMV-specific and functional T cells, whereas off-target vaccine responses activating memory T cells from the related herpesvirus Epstein-Barr virus remained undetectable. Combined safety and immunogenicity results of MVA in allogeneic hematopoietic stem cell transplant (HCT) recipients and Triplex in healthy adults motivated the initiation of a placebo-controlled multicenter trial of Triplex in HCT patients. This trial was registered at www.clinicaltrials.gov as #NCT02506933.

Safety and efficacy of a cytomegalovirus glycoprotein B (gB) vaccine in adolescent girls: A randomized clinical trial.

BACKGROUND: Cytomegalovirus (CMV) is a leading cause of congenital infection and an important target for vaccine development. METHODS: CMV seronegative girls between 12 and 17 years of age received CMV glycoprotein B (gB) vaccine with MF59 or saline placebo at 0, 1 and 6 months. Blood and urine were collected throughout the study for evidence of CMV infection based on PCR and/or seroconversion to non-vaccine CMV antigens. RESULTS: 402 CMV seronegative subjects were vaccinated (195 vaccine, 207 placebo). The vaccine was generally well tolerated, although local and systemic adverse events were significantly more common in the vaccine group. The vaccine induced gB antibody in all vaccine recipients with a gB geometric mean titer of 13,400 EU; 95%CI 11,436, 15,700, after 3 doses. Overall, 48 CMV infections were detected (21 vaccine, 27 placebo). In the per protocol population (124 vaccine, 125 placebo) vaccine efficacy was 43%; 95%CI: -36; 76, p=0.20. The most significant difference was after 2 doses, administered as per protocol; vaccine efficacy 45%, 95%CI: -9; 72, p=0.08. CONCLUSION: The vaccine was safe and immunogenic. Although the efficacy did not reach conventional levels of significance, the results are consistent with a previous study in adult women (Pass et al. N Engl J Med 2009;360:1191) using the same formulation.

Adjunctive therapy with V-5 Immunitor (V5) for the treatment of tuberculosis patients: a meta-analysis.

OBJECTIVE: To evaluate the effectiveness and safety of V-5 immunitor (V5) added to chemotherapy of tuberculosis (TB) patients. METHODS: The databases Medline, Embase, Biosis, Cochrane Central Register of Controlled Trials, SCI, CBM, VIP and CNKI were searched. Randomized controlled trials (RCT) and controlled clinical trials (CCT) of V5 immunitor with or without a placebo-control as adjuvant therapy in the chemotherapy of TB patients were included. Two reviewers independently performed data extraction and quality assessment. Data were analyzed using RevMan 5.3 software by The Cochrane Collaboration. RESULTS: Four studies were included. At the end of the follow-up period, pooled RR (Risk Ratio) and its 95% CI of sputum smear conversion rate were 4.91 (3.32, 7.28) in drug-sensitive, drug-resistant TB patients or HIV-TB co-infection patients. When analyzing inflammation biomarkers including ESR and leukocyte accounts, pooled mean difference and its 95% CI of ESR and leukocyte accounts were -7.62 (-9.55, -5.68) and -2.13 (-2.58, -1.68), respectively. As to body weight, pooled mean difference and its 95% CI were 0.96 (-1.13, 3.05) in TB patients. Two clinical trials were included for analyzing temperature after using V5 immunitor, pooled mean difference and its 95% CI were -0.34 (-0.46, -0.22) in TB patients. These results suggested that V5 immunitor holds important promise in improving sputum conversion to AFB- and inhibiting inflammatory reaction in TB patients, but showed no significant promotion to the increase in body weight based on this meta-analysis. Compared with the control group, V5 immunitor may have some potential in decreasing the temperature of TB patients. No systemic adverse events were reported. CONCLUSION: Added to chemotherapy, V5 immunitor seems to be helpful in the treatment of TB patients in terms of improving sputum conversion and reducing inflammatory reactions.

Induction of cytomegalovirus-specific T cell responses in healthy volunteers and allogeneic stem cell recipients using vaccination with messenger RNA-transfected dendritic cells.

BACKGROUND: Infection with human cytomegalovirus (CMV) is a significant cause of morbidity and mortality in solid organ and hematopoietic stem cell transplant (HSCT) recipients. METHODS: The present study explored the safety, feasibility, and immunogenicity of CMV pp65 messenger RNA-loaded autologous monocyte-derived dendritic cells (DC) as a cellular vaccine for active immunization in healthy volunteers and allogeneic HSCT recipients. Four CMV-seronegative healthy volunteers and three allogeneic HSCT recipients were included in the study. Four clinical-grade autologous monocyte-derived DC vaccines were prepared after a single leukapheresis procedure and administered intradermally at a weekly interval. RESULTS: De novo induction of CMV-specific T-cell responses was detected in three of four healthy volunteers without serious adverse events. Of the HSCT recipients, none developed CMV disease and one of two patients displayed a remarkable threefold increase in CMV pp65-specific T cells on completion of the DC vaccination trial. CONCLUSION: In conclusion, our DC vaccination strategy induced or expanded a CMV-specific cellular response in four of six efficacy-evaluable study subjects, providing a base for its further exploration in larger cohorts.

An attenuated cytomegalovirus vaccine with a deletion of a viral chemokine gene is protective against congenital CMV transmission in a guinea pig model.

Development of a vaccine against congenital cytomegalovirus (CMV) infection is a public health priority, but CMVs encode immune evasion genes that complicate live virus vaccine design. To resolve this problem, this study employed guanosyl phosphoribosyl transferase (gpt) mutagenesis to generate a recombinant guinea pig CMV (GPCMV) with a knockout of a viral chemokine gene, GPCMV MIP (gp1). MIP deletion virus replicated with wild-type kinetics in cell culture but was attenuated in nonpregnant guinea pigs, demonstrating reduced viremia and reduced inflammation and histopathology (compared to a control virus with an intact GPCMV MIP gene) following footpad inoculation. In spite of attenuation, the vaccine was immunogenic, eliciting antibody responses comparable to those observed in natural infection. To assess its protective potential as a vaccine, either recombinant virus or placebo was used to immunize seronegative female guinea pigs. Dams were challenged in the early 3rd trimester with salivary gland-adapted GPCMV. Immunization protected against DNAemia (1/15 in vaccine group versus 12/13 in the control group, P < 0.01). Mean birth weights were significantly higher in pups born to vaccinated dams compared to controls (98.7 g versus 71.2 g, P < 0.01). Vaccination reduced pup mortality, from 35/50 (70%) in controls to 8/52 (15%) in the immunization group. Congenital GPCMV infection was also reduced, from 35/50 (70%) in controls to 9/52 (17%) in the vaccine group (P < 0.0001). We conclude that deletion of an immune modulation gene can attenuate the pathogenicity of GPCMV while resulting in a viral vaccine that retains immunogenicity and demonstrates efficacy against congenital infection and disease.

The next generation recombinant human cytomegalovirus vaccine candidates-beyond gB.

Human cytomegalovirus (HCMV) infects the majority of the global population and persists within the infected host for life; infection of healthy adults rarely leads to severe acute clinical symptoms. In contrast, HCMV is a leading infectious cause of congenital disease and a common cause of complications in transplant recipients. A vaccine to prevent HCMV disease in these populations is a widely recognized medical need. We review recent advances in our understanding of the candidate vaccine antigens and published clinical trial data for the four most recent HCMV vaccine candidates: a gB subunit adjuvanted with MF59, a DNA vaccine expressing gB and pp65, alphavirus replicon particles (VRPs) expressing gB and a pp65-IE1 fusion protein, and a pp65 peptide vaccine. The candidates are safe, although some adverse events were reported for an adjuvanted variant of the pp65 peptide vaccine. The gB/MF59 vaccine elicited strong humoral responses with limited durability. The gB/pp65 DNA vaccine elicited cellular immunity, and the pp65 peptide vaccine elicited modest cellular immunity, but only when formulated with an adjuvant. Only the VRP vaccine expressing gB and pp65-IE1 elicited both humoral and cellular immunity. The gB/MF59 vaccine showed a short-term 50% efficacy at preventing infection of seronegative women and significantly reduced viremia and need for antivirals in solid organ transplant recipients, and the gB/pp65 DNA vaccine showed signs of clinical benefit in hematopoietic stem cell transplant recipients. Importantly, the partial efficacy of the subunit and DNA vaccines is new evidence that both humoral and cellular immunity contribute to controlling HCMV-related disease. These data show the clinical feasibility of a recombinant HCMV vaccine. We discuss areas for potential improvements in the next generation of vaccine candidates.

Clinical evaluation of safety and immunogenicity of PADRE-cytomegalovirus (CMV) and tetanus-CMV fusion peptide vaccines with or without PF03512676 adjuvant.

BACKGROUND: It has been reported that cytomegalovirus (CMV) pp65-specific T cells can protect hematopoietic cell transplant (HCT) recipients from CMV complications. Two candidate CMV peptide vaccines composed of the HLA A*0201 pp65(495-503) cytotoxic CD8(+) T-cell epitope fused to 2 different universal T-helper epitopes (either the synthetic Pan DR epitope [PADRE] or a natural Tetanus sequence) were clinically evaluated for safety and ability to elicit pp65 T cells in HLA A*0201 healthy volunteers. METHODS: Escalating doses (0.5, 2.5, 10 mg) of PADRE or Tetanus pp65(495-503) vaccines with (30 adults) or without (28 adults) PF03512676 adjuvant were administered by subcutaneous injection every 3 weeks for a total of 4 injections. RESULTS: No serious adverse events were reported, although vaccines used in combination with PF03512676 had enhanced reactogenicity. Ex vivo responses were detected by flow cytometry exclusively in volunteers who received the vaccine coadministered with PF03512676. In addition, using a sensitive in vitro stimulation system, vaccine-elicited pp65(495-503) T cells were expanded in 30% of volunteers injected solely with the CMV peptides and in all tested subjects receiving the vaccines coinjected with PF03512676. CONCLUSIONS: Acceptable safety profiles and vaccine-driven expansion of pp65(495-503) T cells in healthy adults support further evaluation of CMV peptide vaccines combined with PF03512676 in the HCT setting. CLINICAL TRIALS REGISTRATION: NCT00722839.

A spread-deficient cytomegalovirus for assessment of first-target cells in vaccination.

Human cytomegalovirus (HCMV) is a human pathogen that causes severe disease primarily in the immunocompromised or immunologically immature individual. To date, no vaccine is available. We describe use of a spread-deficient murine CMV (MCMV) as a novel approach for betaherpesvirus vaccination. To generate a spread-deficient MCMV, the conserved, essential gene M94 was deleted. Immunization with MCMV-DeltaM94 is apathogenic and protective against wild-type challenge even in highly susceptible IFNalphabetaR(-/-) mice. MCMV-DeltaM94 was able to induce a robust CD4(+) and CD8(+) T-cell response as well as a neutralizing antibody response comparable to that induced by wild-type infection. Endothelial cells were identified as activators of CD8(+) T cells in vivo. Thus, the vaccination with a spread-deficient betaherpesvirus is a safe and protective strategy and allows the linkage between cell tropism and immunogenicity. Furthermore, genomes of MCMV-DeltaM94 were present in lungs 12 months after infection, revealing first-target cells as sites of genome maintenance.

Randomized, double-blind, Phase 1 trial of an alphavirus replicon vaccine for cytomegalovirus in CMV seronegative adult volunteers.

Development of a cytomegalovirus (CMV) vaccine is a priority. We evaluated a two component alphavirus replicon particle vaccine expressing CMV gB or a pp65/IE1 fusion protein, previously shown to induce robust antibody and cellular immune responses in mice, in a randomized, double-blind Phase 1 clinical trial in CMV seronegative subjects. Forty subjects received a lower dose (LD) or higher dose (HD) of vaccine or placebo by intramuscular or subcutaneous injection at Weeks 0, 8 and 24. The vaccine was well tolerated, with mild to moderate local reactogenicity, minimal systemic reactogenicity, and no clinically important changes in laboratory parameters. All vaccine recipients developed ex vivo, direct IFN-gamma ELISPOT responses to CMV antigens (maximal mean spot-forming cells per 10(6) PBMC in LD and HD groups of 348 and 504 for pp65, 83 and 113 for IE1, and 138 and 114 for gB), and neutralizing antibodies (maximal geometric mean titer 110 with LD and 218 with HD). Polyfunctional CD4(+) and CD8(+) T cell responses were detected by polychromatic flow cytometry. This alphavirus replicon particle vaccine was safe and induced neutralizing antibody and multifunctional T cell responses against three CMV antigens that are important targets for protective immunity.

Vaccine prevention of maternal cytomegalovirus infection.

BACKGROUND: Congenital infection with cytomegalovirus (CMV) is an important cause of hearing, cognitive, and motor impairments in newborns. METHODS: In this phase 2, placebo-controlled, randomized, double-blind trial, we evaluated a vaccine consisting of recombinant CMV envelope glycoprotein B with MF59 adjuvant, as compared with placebo. Three doses of the CMV vaccine or placebo were given at 0, 1, and 6 months to CMV-seronegative women within 1 year after they had given birth. We tested for CMV infection in the women in quarterly tests during a 42-month period, using an assay for IgG antibodies against CMV proteins other than glycoprotein B. Infection was confirmed by virus culture or immunoblotting. The primary end point was the time until the detection of CMV infection. RESULTS: We randomly assigned 234 subjects to receive the CMV vaccine and 230 subjects to receive placebo. A scheduled interim analysis led to a stopping recommendation because of vaccine efficacy. After a minimum of 1 year of follow-up, there were 49 confirmed infections, 18 in the vaccine group and 31 in the placebo group. Kaplan-Meier analysis showed that the vaccine group was more likely to remain uninfected during a 42-month period than the placebo group (P=0.02). Vaccine efficacy was 50% (95% confidence interval, 7 to 73) on the basis of infection rates per 100 person-years. One congenital infection among infants of the subjects occurred in the vaccine group, and three infections occurred in the placebo group. There were more local reactions (pain, erythema, induration, and warmth) and systemic reactions (chills, arthralgias, and myalgias) in the vaccine group than in the placebo group. CONCLUSIONS: CMV glycoprotein B vaccine has the potential to decrease incident cases of maternal and congenital CMV infection. (ClinicalTrials.gov number, NCT00125502.)

A CMV DNA vaccine primes for memory immune responses to live-attenuated CMV (Towne strain).

CMV-seronegative subjects vaccinated intramuscularly or intradermally with a DNA vaccine encoding pp65, IE1, and gB were administered live-attenuated CMV (Towne) to characterize immune priming by the DNA vaccine. CMV-specific memory T-cells (detected by standard ELISPOT assay in only 20% of subjects) were detected by IFN-gamma cultured ELISPOT assay in 60% of subjects primed intramuscularly and correlated with immune responses after Towne. The median time to first pp65 T-cell and gB antibody response after Towne was 14 days for DNA-primed subjects vs. 28 days for controls administered Towne only (p=0.02 and 0.03, respectively). Furthermore, there was a trend toward more DNA-vaccinated subjects than controls developing a gB-specific IFN-gamma T-cell response after Towne administration (47% vs. 0%, p=0.06).

Safety and immunogenicity of a bivalent cytomegalovirus DNA vaccine in healthy adult subjects.

BACKGROUND: VCL-CB01, a candidate cytomegalovirus (CMV) DNA vaccine that contains plasmids encoding CMV phosphoprotein 65 (pp65) and glycoprotein B (gB) to induce cellular and humoral immune responses and that is formulated with poloxamer CRL1005 and benzalkonium chloride to enhance immune responses, was evaluated in a phase 1 clinical trial. METHODS: VCL-CB01 was evaluated in 44 healthy adult subjects (22 CMV seronegative and 22 CMV seropositive) 18-43 years old. Thirty-two subjects received 1- or 5-mg doses of vaccine on a 0-, 2-, and 8-week schedule, and 12 subjects received 5-mg doses of vaccine on a 0-, 3-, 7-, and 28-day schedule. RESULTS: Overall, the vaccine was well tolerated, with no serious adverse events. Local reactions included mild to moderate injection site pain and tenderness, induration, and erythema. Systemic reactions included mild to moderate malaise and myalgia. All reactions resolved without sequelae. Through week 16 of the study, immunogenicity, as measured by enzyme-linked immunosorbant assay and/or ex vivo interferon (IFN)-gamma enzyme-linked immunospot assay, was documented in 45.5% of CMV-seronegative subjects and in 25.0% of CMV-seropositive subjects who received the full vaccine series, and 68.1% of CMV-seronegative subjects had memory IFN-gamma T cell responses at week 32. CONCLUSION: The safety and immunogenicity data from this trial support further evaluation of VCL-CB01.

Open-label trial of therapeutic immunization with oral V-5 Immunitor (V5) vaccine in patients with chronic hepatitis C.

We evaluated whether V-5 Immunitor (V5)--tableted therapeutic bivalent vaccine comprising heat-inactivated HCV antigens from pooled blood of HBV- and HCV-infected donors - may produce clinical benefit through induction of oral tolerance and reduction of immune-mediated liver injury. Once daily dose of V5 was administered per os to 10 patients with chronic hepatitis C in an open-label study that lasted 1 month. Every patient who entered the study had elevated liver enzyme levels, which at the end of study have decreased in 100% of analyzed patients. The reduction was highly significant, from 157.7+/-73.4 to 49.9+/-43.8 U/L (P=0.0013) and 147.0+/-79.2 to 58.7+/-56.6 U/L (P=0.0132), for ALT and AST, respectively. The AST/ALT ratio has improved from 0.93 to 1.18 (P=0.00058) indicating the reversion of progression to cirrhosis. None of intent-to-treat patients who were anti-HCV antibody positive at study entry, became negative after 1 month on V5 (P=0.998). All patients, except one, reported complete recuperation from hepatitis C-associated clinical symptoms present at baseline (P=0.0016) with Mantel Haenszel's odds ratio 9.4 (P=0.0021) at 95% confidence interval: 2.7

Human CMV vaccine trials: what if CMV caused a rash?

There are no apparent biologic obstacles to immunization against fetal/placental infection with cytomegalovirus (CMV), and vaccine candidates have been developed. The major obstacles for a human CMV vaccine are difficulties associated with the design and execution of efficacy trials. These trials will be prolonged with difficulties in recruiting subjects, and hampered by several factors: First is a lack of public awareness of CMV, making recruitment into vaccine trials difficult. Second is that trials using fetal infection as an endpoint will be prolonged since vaccine administration must occur preconception. Third, behavioral changes by subjects will affect infection rates, and controls for behavioral changes will have to be in place in any clinical trial. Fourth, not all women are at equal risk for CMV infections. High risk women may become infected by contact with young children or via sexual activity. Thus, the mode of acquisition may be a confounding variable in vaccine efficacy trials. In spite of these potential obstacles, successful evaluation of CMV vaccines is possible and likely when considered against similar obstacles encountered by several other recently licensed vaccines.

Vaccine strategies against human cytomegalovirus infection.

Human cytomegalovirus (HCMV) disease is a major cause of morbidity and mortality in neonates and immunocompromised populations, such as transplant recipients and HIV-infected patients. The development of a vaccine to prevent HCMV infection or disease has been assigned the highest priority by the US Institute of Medicine. Although, after 30 years of intensive study, a clinically licensed vaccine is still not available, significant progress has been made in the field of HCMV vaccine development, along with greater understanding of HCMV immunology, molecular biology and pathology. In recent years, new vaccine strategies have been developed that have shown promising results in preclinical studies and are able to induce HCMV-specific immune responses in clinical studies, although efficacy data are not yet available. Here we review the history of HCMV vaccine development and the current strategies in the development of new HCMV vaccines. We propose that research should focus on the development of a vaccine to prevent or control HCMV-related disease rather than to prevent infection, and that discerning strategies should be used for targeting HCMV disease in different clinical settings.

Safety and immunogenicity of Towne cytomegalovirus vaccine with or without adjuvant recombinant interleukin-12.

The Towne, human cytomegalovirus (CMV) vaccine is safe and immunogenic but has not prevented infection at doses tested to date. We administered 3000 pfu Towne CMV vaccine, with or without adjuvant recombinant interleukin-12 (rhIL-12), to CMV-seronegative healthy volunteers and then measured CMV gB-specific IgG titers and CMV-specific CD4+ and CD8+ T cell proliferation and IFNgamma expression after stimulation with whole viral lysate and immunodominant peptide CMV antigens. Adjuvant rhIL-12 at doses up to 2 microg were well-tolerated and associated with (1) dose-related increases in peak anti-CMV gB IgG titers (though not in sustained titers), (2) dose-related increases in the weak CMV viral lysate-specific CD4+ T cell proliferation responses induced by vaccine alone after 360 days of follow-up, and (3) decreases in the very robust CMV IE-specific peak CD4+ T cell and Day 360 CD8+ T cell proliferation responses induced by the vaccine alone. Also, qualitative CD8+ T cell IFNgamma responses to stimulation with the immunodominant CMV antigen, pp65, tended to occur more frequently in vaccinees who received 0.5-2.0 microg rhIL-12 compared to lower dose or no rhIL-12. Thus, adjuvant IL-12 may be a promising strategy for improving antibody and T cell immune responses to a CMV vaccine.

Immunogenicity of a recombinant human cytomegalovirus gB vaccine in seronegative toddlers.

BACKGROUND: Immunization of young children against cytomegalovirus (CMV) might decrease child-to-child and child-to-adult transmission of CMV and thereby reduce maternal infection during pregnancy. We conducted a Phase I trial in CMV-seronegative toddlers to evaluate the reactogenicity and immunogenicity of a CMV gB vaccine administered with MF59, an oil and water adjuvant. METHODS: Eighteen children between 12 and 35 months of age received either 20 microg of CMV gB/MF59 (n = 15) or a control hepatitis A vaccine (n = 3) at 0, 1 and 6 months. The study was open-label for the first six children and then observer-blinded and randomized. Children were monitored for local and systemic reactions and for the development of antibodies to the envelope protein gB and CMV-neutralizing antibodies. RESULTS: Adverse reactions were uncommon and mild. Two children were excluded from the immunogenicity analysis because they had serologic evidence of CMV infection. Reciprocal geometric mean neutralizing titers were: 0 preimmunization (n = 18); 90 (range, 53 to 188) after Dose 2 (n = 6); and 638 (range, 210 to 1645) 1 month after Dose 3 (n = 13). The reciprocal geometric mean neutralizing titers of antibody to gB by EIA were: 0 preimmunization (n = 18); 857 (range, 307 to 2073) after Dose 1 (n = 12); 27 457 (range, 9312 to 55,080) after Dose 2 (n = 6); and 98,264 (range, 35,480 to 228,780) 1 month after Dose 3 (n = 5). After Dose 3 antibody responses of toddlers were greater than those of naturally infected adults and were notably higher than among 149 adults given 3 doses of the same vaccine in other trials. CONCLUSION: The CMV gB vaccine is well-tolerated and highly immunogenic in toddlers.