Correlates of protection against SARS-CoV-2 infection and COVID-19 disease.

Antibodies against epitopes in S1 give the most accurate CoP against infection by the SARS-CoV-2 coronavirus. Measurement of those antibodies by neutralization or binding assays both have predictive value, with binding antibody titers giving the highest statistical correlation. However, the protective functions of antibodies are multiple. Antibodies with multiple functions other than neutralization influence efficacy. The role of cellular responses can be discerned with respect to CD4+ T cells and their augmentation of antibodies, and with respect to CD8+ cells with regard to control of viral replication, particularly in the presence of insufficient antibody. More information is needed on mucosal responses.

Can We Prevent Congenital Infection by Cytomegalovirus?

Cytomegalovirus is now the most common cause of congenital infections, leading to numerous abnormalities. After 50 years of failed attempts to develop a licensed vaccine to be given to women before pregnancy, modern platforms for vaccine construction allow hope for an effective prophylactic.

Rubella Eradication: Not Yet Accomplished, but Entirely Feasible.

Rubella virus is the most teratogenic virus known to science and is capable of causing large epidemics. The RA 27/3 rubella vaccine, usually combined with measles vaccine, has eliminated rubella and congenital rubella syndrome from much of the world, notably from the Western Hemisphere. Except in immunosuppressed individuals, it is remarkably safe. Together with rubella vaccine strains used in China and Japan, eradication of the rubella virus is possible, indeed more feasible than eradication of measles or mumps.

The Facts About Vaccine Safety.

The Vaccine Compensation System evaluates true and false associations between vaccination and adverse events. The data from the system enable the calculation of the risk of serious adverse events per million doses given of each vaccine.

Viewpoint of a WHO Advisory Group Tasked to Consider Establishing a Closely-monitored Challenge Model of Coronavirus Disease 2019 (COVID-19) in Healthy Volunteers.

WHO convened an Advisory Group (AG) to consider the feasibility, potential value, and limitations of establishing a closely-monitored challenge model of experimental severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) in healthy adult volunteers. The AG included experts in design, establishment, and performance of challenges. This report summarizes issues that render a COVID-19 model daunting to establish (the potential of SARS-CoV-2 to cause severe/fatal illness, its high transmissibility, and lack of a "rescue treatment" to prevent progression from mild/moderate to severe clinical illness) and it proffers prudent strategies for stepwise model development, challenge virus selection, guidelines for manufacturing challenge doses, and ways to contain SARS-CoV-2 and prevent transmission to household/community contacts. A COVID-19 model could demonstrate protection against virus shedding and/or illness induced by prior SARS-CoV-2 challenge or vaccination. A limitation of the model is that vaccine efficacy in experimentally challenged healthy young adults cannot per se be extrapolated to predict efficacy in elderly/high-risk adults.

Complex immune correlates of protection in HIV-1 vaccine efficacy trials.

Development of an efficacious HIV-1 vaccine is a major priority for improving human health worldwide. Vaccine-mediated protection against human pathogens can be achieved through elicitation of protective innate, humoral, and cellular responses. Identification of specific immune responses responsible for pathogen protection enables vaccine development and provides insights into host defenses against pathogens and the immunological mechanisms that most effectively fight infection. Defining immunological correlates of transmission risk in preclinical and clinical HIV-1 vaccine trials has moved the HIV-1 vaccine development field forward and directed new candidate vaccine development. Immune correlate studies are providing novel hypotheses about immunological mechanisms that may be responsible for preventing HIV-1 acquisition. Recent results from HIV-1 immune correlates work has demonstrated that there are multiple types of immune responses that together, comprise an immune correlate-thus implicating polyfunctional immune control of HIV-1 transmission. An in depth understanding of these complex immunological mechanisms of protection against HIV-1 will accelerate the development of an efficacious HIV-1 vaccine.

Preventing Infection by Human Cytomegalovirus.

The way to a successful vaccine against human cytomegalovirus is hampered by the peculiar biology of this infection. However, some candidate vaccines have been shown to protect seronegative women and transplant recipients, and we should know soon whether they can prevent congenital infection.

Review of Mathematical Models of Vaccination for Preventing Congenital Cytomegalovirus Infection.

BACKGROUND: Several cytomegalovirus (CMV) vaccine candidates are under development. To reduce the burden of congenital CMV infection, potential strategies under consideration include vaccination of adult women, adolescent girls, and/or young children (both sexes). METHODS: We reviewed 5 studies that used infectious disease modeling to assess the potential impact of vaccination for preventing congenital CMV infection. All models assumed CMV vaccination would prevent primary infection and 2 models also assumed prevention of reinfections and reactivations. RESULTS: Despite differences in structure, assumptions, and population data, infant vaccination (both sexes) was the optimal strategy in all models, but in 1 model vaccinating seronegative women at 19-21 years of age was also optimal (for duration of vaccine protection ≥8 years). In 3 models, infant vaccination increased average age at primary infection as a result of decreased secondary transmission (herd immunity) combined with waning vaccine-induced immunity. This effect could increase the risk of congenital CMV infections in populations where primary CMV infection occurs early in childhood but could be minimized by administering a second dose of vaccine during adolescence. CONCLUSIONS: Understanding vaccine efficacy and duration of immunity, and how these might vary depending on CMV serostatus and age at vaccination, will be key to defining CMV vaccination strategies.

The Status of Vaccine Development Against the Human Cytomegalovirus.

Numerous candidate vaccines against cytomegalovirus (CMV) infection and disease are in development. Whereas the previous article [1] provides background and opinions about the issues relating to vaccination, this article provides specifics about the vaccines in active development, as reported at a National Institutes of Health-sponsored meeting in Bethesda on September 4-6, 2018. Here, vaccine developers provide synopses of their candidate vaccines to immunize women to protect against congenital CMV disease and to prevent the consequences of CMV disease in recipients of transplanted organs or hematopoietic stem calls. The projects are presented here roughly in the descending order of their stage of development in the opinion of the first author.

CEPI: Driving Progress Toward Epidemic Preparedness and Response.

The Coalition for Epidemic Preparedness Innovations (CEPI) was formed in the aftermath of the 2014-2015 Ebola outbreak in west Africa to support the development of vaccines that could improve the world's preparedness against outbreaks of epidemic infectious diseases. Since its launch in 2017, CEPI has mobilized more than US$750 million to support its mission to develop vaccines against agents such as Lassa virus, Middle East respiratory syndrome coronavirus, and Nipah virus, as well as several rapid-response vaccine platforms to accelerate response times to unexpected epidemic threats. CEPI has also played a leading role in fostering institutional partnerships between public- and private-sector organizations to optimize allocation of resources for vaccine development against its priority pathogens. CEPI's priorities include diversification of its current vaccine research and development investment portfolio to include additional pathogens, such as Rift Valley fever and chikungunya; establishment of technical and regulatory pathways for vaccine development across CEPI's portfolio; development of sustainable manufacturing solutions for vaccine candidates nearing completion of safety and immunogenicity testing in humans; and creation of investigational stockpiles of its vaccine candidates for use in emergency situations. This commentary provides an overview of the global health challenges CEPI was established to address and its achievements to date, and indicates priorities for funding and coordination in the coming years.

Advancing Our Understanding of Protective Maternal Immunity as a Guide for Development of Vaccines To Reduce Congenital Cytomegalovirus Infections.

Human cytomegalovirus (HCMV) is the most common congenitally transmitted pathogen worldwide, impacting an estimated 1 million newborns annually. Congenital HCMV (cCMV) infection is a major global contributor to long-term neurologic deficits, including deafness, microcephaly, and neurodevelopmental delay, as well as to fetal loss and occasional infant mortality. Accordingly, design of a maternal vaccine to prevent cCMV continues to be a top public health priority. Nevertheless, we remain without a licensed vaccine. Maternal immunity provides partial protection, as the risk of vertical HCMV transmission from chronically infected mothers is reduced compared to settings in which the mother is newly infected during pregnancy. Therefore, an understanding of the maternal immune correlates of protection against cCMV is critical to informing design of an efficacious maternal vaccine. Although vaccine development is being assiduously pursued by a large number of pharmaceutical manufacturers, biotechnology organizations, and academic researchers, some pessimism has been expressed regarding the issue of whether a vaccine to protect against cCMV is possible. This pessimism is based on observations that natural immunity is not completely protective against maternal reinfection and congenital transmission. However, we assert that optimism regarding vaccine development is indeed justified, on the basis of accruing evidence of immune correlates of protection-readily achievable by vaccination-that are associated with reduced transmission of HCMV to the fetus in seronegative women. In light of the substantial burden on society conferred by cCMV infection, even a modest reduction in the occurrence of this fetal disease is an important public health goal and justifies aggressive clinical evaluation of vaccines currently in the pipeline.

Increasing Complexity of Vaccine Development.

Vaccines already developed have been enormously successful. However, the development of future vaccines requires solution of a number of immunologic problems, including pathogen variability, short effector memory, evoking functional responses, and identification of antigens that generate protective responses. In addition, different populations may respond differently to the same vaccine because of genetic, age, or environmental factors.