Safety and Immunogenicity of a Messenger RNA-Based Cytomegalovirus Vaccine in Healthy Adults: Results From a Phase 1 Randomized Clinical Trial.

BACKGROUND: This phase 1 trial evaluated the safety, reactogenicity, and immunogenicity of mRNA-1647, a messenger RNA (mRNA)-based cytomegalovirus (CMV) vaccine, in CMV-seronegative and -seropositive adults. METHODS: Participants were randomly assigned to receive 30, 90, 180, or 300 µg of mRNA-1647 or placebo on a 0-, 2-, and 6-month schedule and followed for 12 months after the last dose. RESULTS: A total of 154 (80 CMV-seronegative and 74 CMV-seropositive) participants were enrolled; 118 participants were randomized to mRNA-1647 and 36 to placebo. Mean (standard deviation) age was 32.5 (8.6) and 35.1 (8.9) years in the placebo and mRNA-1647 groups, respectively, in phase B (63% and 64% female) and 42.5 (6.2) and 33.3 (8.7) years, respectively, in phase C (2% and 16% female). No deaths, related serious adverse events, or adverse events of special interest were reported. Most adverse reactions were grade ≤2 severity. Increased neutralizing antibody, binding antibody, and antigen-specific cell-mediated responses were observed across mRNA-1647 treatment groups, regardless of CMV serostatus. CONCLUSIONS: This phase 1, first-in-human trial demonstrated that mRNA-1647 has an acceptable safety profile in adults and elicits humoral and cellular immune responses. Clinical Trials Registration. NCT03382405.

Cytomegalovirus (CMV) is a common virus that can cause severe illness in people with weakened immune systems and in babies infected from a mother with a CMV infection during pregnancy. To date, there is no approved vaccine available to prevent CMV infection. This study in healthy adult participants is the first to test an investigational CMV vaccine called mRNA-1647, a messenger RNA (mRNA)-based vaccine developed using a technology similar to that used for vaccines to prevent COVID-19. Here, we evaluated the safety of mRNA-1647 and whether mRNA-1647 can increase levels of antibodies and immune cells (parts of the immune system that help defend against a foreign invader such as a virus). Most of the side effects observed after mRNA-1647 injection were mild; these included common reactions that occur after vaccination such as pain at the site of vaccination, headache, tiredness, muscle aches and pains, and chills. Levels of antibodies and immune cells in the blood increased after vaccination with mRNA-1647. Together, these findings show that mRNA-1647 was well tolerated and produced an immune response in adults, and support continued research on mRNA-1647 as a potential approach to prevent CMV infection.

A Qualitative Assessment of Clinical Practice Guidelines and Patterns for Congenital Cytomegalovirus in the United States.

Cytomegalovirus (CMV) infection during pregnancy may result in long-term health problems for children with congenital CMV (cCMV). Currently, no prevention or treatment interventions are approved by the Food and Drug Administration for a cCMV indication. Healthcare provider and public awareness is low, and formal clinical practice guidelines and local practice patterns vary. A pilot study of eight cCMV experts was performed using qualitative semi-structured interviews to better understand clinical practice guidelines and patterns in the United States. Results from participant interviews highlighted the need for better prenatal diagnostic techniques, broader neonatal screening opportunities, and more robust evidence supporting intervention strategies. Healthcare provider and public partnerships are essential for advancing cCMV guidelines and improving care delivery. Our results provide a preliminary knowledge base and framework for developing a consensus cCMV research agenda to address evidence gaps that limit the revision of clinical practice guidelines. The changes in clinical practice patterns that may arise as a result of further research have the potential to reduce risk during pregnancy and improve care for children with cCMV infection.

A systematic literature review of the economic and healthcare resource burden of cytomegalovirus.

OBJECTIVE: Cytomegalovirus (CMV) can infect individuals at any age, including infants, who may contract it from infected mothers (congenital CMV [cCMV]). Whereas CMV infection is typically asymptomatic or causes mild illness in healthy individuals, infection can result in severe outcomes in immunocompromised individuals and in infants with cCMV. This systematic review aims to characterize the economic impact of CMV and cCMV infections. METHODS: Medline, Embase, and LILACS databases were searched for publications reporting the economic impact of cCMV and CMV infections across all age groups. Manuscripts published between 2010 and 2020 from Australia, Latin America, Canada, Europe, Israel, Japan, the United States, and global (international, worldwide) studies were included; congress materials were excluded. Outcomes of interest included cCMV- and CMV-attributable direct costs/charges, resource utilization, and indirect/societal costs. RESULTS: Of 751 records identified, 518 were excluded based on duplication, population, outcome, study design, or country. Overall, 55 articles were eligible for full-text review; 25 were further excluded due to population, outcome, study design, or congress abstract. Two publications were additionally identified, resulting in economic impact data compiled from 32 publications. Of these, 24 publications reported cost studies of cCMV or CMV, including evaluation of direct costs/charges, healthcare resource utilization, and indirect/societal costs, and 7 publications reported economic evaluations of interventions. The populations, methods and outcomes used across these studies varied widely. CONCLUSIONS: CMV and cCMV infections impose a considerable economic impact on different countries, populations, and outcomes. There are substantial evidence gaps where further research is warranted.

A systematic literature review on the humanistic burden of cytomegalovirus.

OBJECTIVE: Cytomegalovirus (CMV) infection is typically asymptomatic in healthy individuals; however, certain populations are vulnerable to infection and may develop serious sequelae. CMV infection may also have a broad impact on humanistic outcomes, including patient health status and quality of life (QoL). We conducted a systematic literature review (SLR) to describe the global humanistic burden of CMV and congenital CMV (cCMV) infections across all age groups. METHODS: Medline, Embase, and LILACS were searched to identify studies on humanistic outcomes following CMV infection, including health status/QoL and any outcomes in domains such as auditory performance, cognitive ability, developmental status, intelligence, language, memory, mental health, motor performance, social communication, speech, and vocabulary. The SLR included articles published from 2000 to 2020 and focused geographically on Australia, Europe, Israel, Japan, Latin America, and North America. RESULTS: Sixty-three studies met the inclusion criteria. In general, individuals with symptomatic cCMV infection experience a greater burden of disease and more substantial impact on QoL versus those with asymptomatic cCMV infection. Children with hearing loss due to cCMV infection, both symptomatic and asymptomatic, showed improved auditory outcomes following cochlear implantation. Newborns, infants, and children with cCMV infections had worse cognitive outcomes in psychological development, sequential and simultaneous processing, phonological working memory, and attention control versus age-matched controls without cCMV infection. CMV infection was also associated with cognitive decline in elderly populations. CONCLUSIONS: CMV infection can have substantial, lifelong, heterogenous impacts on humanistic outcomes, including health status and QoL, which should be considered when developing and implementing treatment and prevention strategies.

A systematic literature review of the global seroprevalence of cytomegalovirus: possible implications for treatment, screening, and vaccine development.

BACKGROUND: Cytomegalovirus (CMV) is a common pathogen that affects individuals of all ages and establishes lifelong latency. Although CMV is typically asymptomatic in healthy individuals, infection during pregnancy or in immunocompromised individuals can cause severe disease. Currently, treatments are limited, with no prophylactic vaccine available. Knowledge of the current epidemiologic burden of CMV is necessary to understand the need for treatment and prevention. A systematic literature review (SLR) was conducted to describe the most recent epidemiologic burden of CMV globally. METHODS: Medline, Embase, and LILACS were searched to identify data on CMV prevalence, seroprevalence, shedding, and transmission rates. The SLR covered the time period of 2010-2020 and focused geographically on Australia, Europe, Israel, Japan, Latin America (LATAM), and North America. Studies were excluded if they were systematic or narrative reviews, abstracts, case series, letters, or correspondence. Studies with sample sizes < 100 were excluded to focus on studies with higher quality of data. RESULTS: Twenty-nine studies were included. Among adult men, CMV immunoglobulin G (IgG) seroprevalence ranged from 39.3% (France) to 48.0% (United States). Among women of reproductive age in Europe, Japan, LATAM, and North America, CMV IgG seroprevalence was 45.6-95.7%, 60.2%, 58.3-94.5%, and 24.6-81.0%, respectively. Seroprevalence increased with age and was lower in developed than developing countries, but data were limited. No studies of CMV immunoglobulin M (IgM) seroprevalence among men were identified. Among women of reproductive age, CMV IgM seroprevalence was heterogenous across Europe (1.0-4.6%), North America (2.3-4.5%), Japan (0.8%), and LATAM (0-0.7%). CMV seroprevalence correlated with race, ethnicity, socioeconomic status, and education level. CMV shedding ranged between 0% and 70.2% depending on age group. No findings on CMV transmission rates were identified. CONCLUSIONS: Certain populations and regions are at a substantially higher risk of CMV infection. The extensive epidemiologic burden of CMV calls for increased efforts in the research and development of vaccines and treatments. TRIAL REGISTRATION: N/A.