Lyme disease is caused by Borrelia species that are transmitted by Ixodes ticks prevalent in parts of the United States and Europe. A Lyme vaccine containing the outer surface protein A (OspA) antigens from the single Borrelia species most prevalent in the United States was marketed in the 1990s, but was withdrawn because of unproven concerns about safety, which led to insufficient sales. Since then, the incidence of Lyme disease has increased in the United States owing to the geographical spread of infected ticks. Lyme disease due to multiple different species of Borrelia is also widely prevalent in many European countries. New Lyme vaccines, using OspA antigens from multiple species of American and European Borrelia, are in advanced clinical development, and one such vaccine is in phase 3 trials. When licensed, new vaccines are likely to have an impact in preventing Lyme disease, although the need for periodic boosters remains to be defined.

From the *Children's Hospital of Philadelphia, University of Pennsylvania, Doylestown, Pennsylvania Accepted for publication March 7, 2025 The authors have no funding or conflicts of interest to disclose. *Address for correspondence: Children's Hospital of Philadelphia, University of Pennsylvania, Vaxconsult, 4650 Wismer Rd., Doylestown, PA 18902. E-mail: [email protected].

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.

Vaccines based on messenger RNA technology have been tremendously successful, but their properties are not necessarily ideal for all pathogens. There is a risk that concentration on that technology alone for new vaccine development will ignore older technologies that have properties giving broader and more persistent protection.

In February 2023, a meeting about correlates of protection (CoPs) against COVID-19 was organized by the International Alliance for Biological Standardization, the European Plotkin Institute for Vaccinology, and Vaccinopolis. The meeting aimed at reviewing the evidence, drawing conclusions, and identifying knowledge gaps. Collection of evidence is not straightforward. Neutralizing antibodies correlate with protection and are used for immunobridging studies within and between vaccine platforms for approval of new COVID-19 vaccines. In preparation for the next pandemic, it is vital that rapidly authorized initial vaccines are available to perform immunobridging studies very early. Additional components of the immune response likely contribute to protection against symptomatic infection. Current evidence is strongest for T lymphocytes and binding antibodies. Further studies are needed to consolidate this evidence and define their potential role in the evaluation of vaccines. For evaluation of mucosal vaccines, identifying CoPs against infection and transmission is key; further research is needed to identify and standardize methods suitable for clinical studies. CoPs for broadly protective beta-coronavirus vaccines remain a critical area of research. The knowledge, expertise, and capacity exist to conduct clinical studies using different designs in different populations to discover and validate CoPs, facilitating and accelerating evaluation of novel vaccines/vaccination platforms.

Mumps virus (MuV) is a highly contagious paramyxovirus that is endemic in most regions of the world and continues to cause outbreaks even in highly immunized populations. Outbreaks of mumps in countries with high measles, mumps, and rubella vaccination coverage have been attributed to waning immunity and antigenic differences between the Jeryl Lynn vaccine strain (genotype A) and circulating wild-type viruses. To obtain a subunit vaccine, we used structure-based design to engineer the mumps fusion (F) glycoprotein stabilized in its prefusion conformation (Pre-F) as well as a chimeric immunogen comprising Pre-F linked to mumps hemagglutinin neuraminidase (HN); in mice, both Pre-F antigen and the chimeric antigen elicited potent cross-reactive plaque reducing neutralizing titers to genotypes A, G, and H mumps. A crystal structure of mumps Pre-F at 2.16 Å resolution validated the stabilization strategy, while a post-fusion form of F was engineered as a comparator. Monoclonal antibodies to mumps Pre-F and HN were isolated from immunized mice; 7 of 14 Pre-F-specific antibodies and 9 of 15 HN-specific antibodies were capable of neutralizing genotype G MuV with a range of potencies. Additionally, 7 of 14 Pre-F-specific antibodies neutralized genotype A mumps. Structural and binding analyses of Pre-F-specific antibodies revealed binding to four discrete neutralizing antigenic sites and binding analyses of HN-specific antibodies revealed binding to five discrete neutralizing antigenic sites. Overall, the PreF and the chimeric Pre-F/HN immunogens are promising candidates to boost MMR-elicited immunity to mumps or as a next-generation vaccine.

Funding Postauthorization Vaccine-Safety Science The slow speed of science contributes to public concern about vaccines and reduced immunization coverage. Postauthorization safety research requires timely funding linked to the introduction of new vaccines.

On 27–29th of September 2022, Wellcome convened an international multi-stakeholder workshop to discuss the use of Correlates of Protection (CoP) to accelerate vaccine development, the hybrid format meeting was attended by 80 delegates including developers, manufacturers, regulators, public health officials and policy-makers from 17 countries, including 7 LMIC’s.

From the Department of Pediatrics, University of Pennsylvania, Doylestown, Pennsylvania. Accepted for publication May 16, 2024 The author has no funding or conflicts of interest to disclose. Address for correspondence: Stanley A. Plotkin, MD, Department of Pediatrics, University of Pennsylvania, 4650 Wismer Road, Doylestown, PA 18902. E-mail: [email protected].

*From the University of Pennsylvania, Doylestown, Pennsylvania †Children's Hospital of Philadelphia, Philadelphia, Pennsylvania ‡Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Accepted for publication February 26, 2024 The authors have no funding or conflicts of interest to disclose. Address for correspondence: Stanley A. Plotkin, MD, 4650 Wismer Rd., Doylestown, PA 18902. E-mail: [email protected].

Journal Article Corrected proof Georges Peter, MD (1938-2024) Get access Stanley Plotkin Stanley Plotkin University of Pennsylvania, Philadelphia stanley.plotkin@vaxconsult.com Search for other works by this author on: Oxford Academic PubMed Google Scholar Journal of the Pediatric Infectious Diseases Society, piae020, https://doi.org/10.1093/jpids/piae020 Published: 10 April 2024 Article history Received: 05 February 2024 Editorial decision: 20 February 2024 Accepted: 05 April 2024 Corrected and typeset: 10 April 2024 Published: 10 April 2024

Congenital cytomegalovirus (cCMV) is the most common infectious cause of disability in children. The major theme of this National Institute of Allergy and Infectious Diseases (NIAID) workshop, “CMV Vaccine Development—How Close Are We?”, was to report progress on the development of a pre-conception vaccine that could confer protective immunity for women of child-bearing age. Such a vaccine could result in a reduced cCMV disease burden, although other populations, including solid organ transplant and hematopoietic stem cell transplant patients, could benefit as well. To frame the compelling need for a cCMV vaccine, a keynote lecture by Dr. Megan Pesch, immediate past-president of the National CMV Foundation and a leading cCMV researcher from the University of Michigan, was given. This manuscript provides a summary of Dr. Pesch’s presentation from this workshop, which was written as the introductory conference report for the meeting.

Vaccines have a history that started late in the 18th century. From the late 19th century, vaccines could be developed in the laboratory. However, in the 20th century, it became possible to develop vaccines based on immunologic markers. In the 21st century, molecular biology permits vaccine development that was not possible before.

Supplemental Figure 1 - Rates of CIN2/3 regression (primary endpoint) or CIN2/3 regression concomitant with clearance of HPV16 and/or HPV18 infection (secondary endpoint) in the Per Protocol population of the Phase IIb study of VGX-3100 for the treatment of biopsy proven CIN2/3 with documented HPV16 and/or HPV18 infection. Supplemental Figure 2 - Immunohistochemical analysis of CD8 infiltration at study start. The left panel shows the frequency of CD8 positive cells/mm2 as broken out by achievement of the primary endpoint of histopathological regression of CIN2/3 to CIN1 or WNL. The right panel shows the frequency of CD8 positive cells/mm2 as broken out by achievement of the primary endpoint of histopathological regression of CIN2/3 to CIN1 or WNL concomitant with elimination of HPV16/18 infection. Supplemental Figure 3 - CD137 is a marker for antigen specificity and activation on CD8+ T cells. A representative patient stain is shown for CD137 expression prior to (top) and following dosing (bottom) with VGX-3100. Whole unfractionated PBMCs were incubated with DMSO (vehicle control), OVA peptide (peptide control) HPV16 antigens, HPV18 antigens or Concanavalin A (positive control) for 120 hours. Supplemental Figure 4 - Breakdown of HPV16 and HPV18 positivity at enrollment of the study. Patients are represented as being HPV16 positive only (HPV16+ and HPV18-), HPV18 positive only (HPV16- and HPV18+) or positive for both viruses (HPV16+ and HPV18+). The bottom row represents the total patients in the study. Columns are broken into placebo and VGX-3100 cohorts and total patients in the study.