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Correlates of protection are key for vaccine development against any pathogen. In this paper we summarize recent information about correlates for vaccines against dengue, Ebola, influenza, pneumococcal, respiratory syncytial virus, rotavirus, shigella, tuberculosis and Zika virus.

A correlate of protection (CoP) is urgently needed to expedite development of additional COVID-19 vaccines to meet unprecedented global demand. To assess whether antibody titers may reasonably predict efficacy and serve as the basis of a CoP, we evaluated the relationship between efficacy and in vitro neutralizing and binding antibodies of 7 vaccines for which sufficient data have been generated. Once calibrated to titers of human convalescent sera reported in each study, a robust correlation was seen between neutralizing titer and efficacy (ρ = 0.79) and binding antibody titer and efficacy (ρ = 0.93), despite geographically diverse study populations subject to different forces of infection and circulating variants, and use of different endpoints, assays, convalescent sera panels and manufacturing platforms. Together with evidence from natural history studies and animal models, these results support the use of post-immunization antibody titers as the basis for establishing a correlate of protection for COVID-19 vaccines.

The pursuit of a vaccine against the human cytomegalovirus (HCMV) has been ongoing for more than 50 years. HCMV is the leading infectious cause of birth defects, including damage to the brain, and is a common cause of complications in organ transplantation. The complex biology of HCMV has made vaccine development difficult, but a recent meeting sponsored by the National Institute of Allergy and Infectious Diseases in September of 2023 brought together experts from academia, industry, and federal agencies to discuss progress in the field. The meeting reviewed the status of candidate HCMV vaccines under study and the challenges in clinical trial design in demonstrating efficacy against congenital CMV infection or the reduction of HCMV disease following solid organ transplantation or hematopoietic stem cell transplantation. Discussion in the meeting revealed that, with the numerous candidate vaccines that are under study, it is clear that a safe and effective HCMV vaccine is within reach. Meeting attendees achieved a consensus opinion that even a partially effective vaccine would have a major effect on the global health consequences of HCMV infection.

Correlates of protection (CoPs) are increasingly important in the development and licensure of vaccines. Although the study of CoPs was initially directed at identifying a single immune function that could explain vaccine efficacy, it has become increasingly clear that there are often multiple functions responsible for efficacy. This review is meant to supplement prior articles on the subject, illustrating both simple and complex CoPs.

Vaccines are one of the most effective tools to protect against infectious diseases. Unfortunately, vaccines for diseases with the highest global health burdens, such as HIV, malaria, and tuberculosis, are not yet available. Koff et al. ( 1232910 ) review the latest advances in vaccine development and why these particular diseases remain such a challenge. Respiratory syncytial virus (RSV) is a serious cause of morbidity and mortality in infants and young children worldwide. Although a prophylactic antibody is available for children at high risk, a vaccine is much needed. As a potential step toward this goal, McLellan et al. (p. 1113 , published online 25 April) solved the cocrystal structure of a neutralizing antibody (D25) bound to the prefusion F protein of RSV. Knowledge of the structure of the prefusion protein should help to guide vaccine design and the development of additional therapeutics. Vaccines are among the greatest successes in the history of public health. However, past strategies for vaccine development are unlikely to succeed in the future against major global diseases such as AIDS, tuberculosis, and malaria. For such diseases, the correlates of protection are poorly defined and the pathogens evade immune detection and/or exhibit extensive genetic variability. Recent advances have heralded in a new era of vaccine discovery. However, translation of these advances into vaccines remains impeded by lack of understanding of key vaccinology principles in humans. We review these advances toward vaccine discovery and suggest that for accelerating successful vaccine development, new human immunology–based clinical research initiatives be implemented with the goal of elucidating and more effectively generating vaccine-induced protective immune responses.

In several prior articles I have attempted to analyze and simplify the subject of immunological functions induced by vaccination that correlate with protection against later exposure to pathogens. Other authors have also written on the subject, and recently we jointly proposed terminology to bring some semantic clarity to the field. The generalization that vaccine-induced antibodies prevent acquisition whereas cellular immune functions clear infection still holds true, but that simple distinction becomes blurred in many instances. Specific antibody and cellular responses are multiple and redundant, so that vaccines for some pathogens protect through more than 1 immune function. Thus, this article aims in the direction opposite to simplicity to depict the complexity of correlates, or rather the complexity of mechanistic immune functions that contribute to protection. Nonmechanistic correlates that are practically useful but not truly protective will be mentioned in passing.

Use of recently licensed vaccines against Neisseria meningitidis serogroup B (NmB) will depend partly on disease burden estimates. We systematically reviewed NmB incidence and mortality worldwide between January, 2000, and March, 2015, incorporating data from 37 articles and 12 websites. Most countries had a yearly invasive NmB incidence of less than 2 per 100 000 people. Within these relatively low incidence rates (compared with common causes of invasive bacterial diseases), substantial variation was detected between countries, with a notably higher incidence in Australia, Europe, North America, and South America. China and India had reports only of sporadic cases, and except for South Africa, sub-Saharan Africa showed a near absence of disease. In countries with consistently collected data, NmB incidence has tended to decrease, even as the proportion of invasive meningococcal disease cases caused by serogroup B has increased. With few exceptions, case-fatality ratios were fairly consistent, ranging between 3% and 10%. In high-income countries, incidence rates of NmB were relatively low compared with other vaccine-preventable diseases and might be decreasing. High case-fatality ratios, substantial disease-related morbidity, and the threat of outbreaks could nevertheless make NmB an attractive target for preventive and reactive immunisation programmes. The low availability of data from low-income and middle-income countries suggests the need for improved surveillance before vaccination strategies are designed.

The immune system is redundant, and B and T cells collaborate. However, almost all current vaccines work through induction of antibodies in serum or on mucosa that block infection or interfere with microbial invasion of the bloodstream. To protect, antibodies must be functional in the sense of neutralization or opsonophagocytosis. Correlates of protection after vaccination are sometimes absolute quantities but often are relative, such that most infections are prevented at a particular level of response but some will occur above that level because of a large challenge dose or deficient host factors. There may be >1 correlate of protection for a disease, which we term “cocorrelates.” Either effector or central memory may correlate with protection. Cell-mediated immunity also may operate as a correlate or cocorrelate of protection against disease, rather than against infection. In situations where the true correlate of protection is unknown or difficult to measure, surrogate tests (usually antibody measurements) must suffice as predictors of protection by vaccines. Examples of each circumstance are given.

Multiple candidates have been proposed and many are in clinical trials, but the question remains as to whether emergency use of a SARS-2 vaccine should await collection of controlled data from large populations that are experiencing epidemic SARS-2 disease or whether to expedite vaccination by moving quickly through animal studies and doing human challenge studies in volunteers [4]. Volunteers might include those who are at high risk of exposure to the virus in the ordinary course of their work or living arrangements. [...]regulators and ethicists should take into account the time required for an efficacy study and the likelihood that control groups in typical phase 3 efficacy studies of SARS-2 vaccines will suffer more deaths than in carefully done human challenges, to say nothing about simultaneous deaths in people not in the studies exposed to circulating virus. [...]it would be possible for regulators to allow emergency use based on the results of challenge studies, and to continue collecting data in the usual fashion for licensure at a later date.

The rapid identification of a correlate of protection for Covid-19 vaccines — on the basis of several harmonized randomized phase 3 trials using common validated assays — constitutes an important success in vaccinology.