This Week in Virology (TWiV) episode 1267 provides a Halloween-themed introduction before delving into two significant scientific papers and relevant news. The first major discussion is a meta-analysis on the therapeutic use of the Gardasil-9 HPV vaccine in adult women who are already HPV-positive or have confirmed cervical lesions (SIL). The review of seven studies suggests that vaccination in this population is linked to a higher rate of viral clearance, reduced progression of lesions, and lower recurrence rates after surgical excision, challenging the vaccine's traditional role as purely prophylactic.
The second half of the scientific discussion focuses on a study identifying human monoclonal antibodies against the monkeypox virus (mpox) A35 protein. Isolated from a convalescent individual, these antibodies (EV35-2, -6, and -7) demonstrated potent prophylactic and therapeutic efficacy in mouse models against lethal orthopoxvirus infections. Structural analysis revealed they target a highly conserved epitope in the A35 dimer groove. The study also links the presence of similar antibodies in human sera to better clinical outcomes, highlighting A35 as a critical target for next-generation therapies. The episode also briefly covers news stories on the endangered status of long-tailed macaques used in research and the first-ever discovery of breeding mosquitoes in Iceland.
TWiV 1267: Therapeutic Vaccines and Mpox Antibodies
5:53 Endangered Research Monkeys: The hosts discuss a report from the International Union for Conservation of Nature (IUCN) upholding the "endangered" status of long-tailed macaques. This is significant because these monkeys are common in biomedical research, and the classification could complicate future studies. The conversation touches on the ethical dilemmas and necessity of animal research.
13:52 Mosquitoes in Iceland: A news story reports the first-ever discovery of a breeding population of mosquitoes (Culiseta annulata) in Iceland. The hosts discuss the likely connection to climate change, as the warming environment allows new species to survive in previously inhospitable regions.
17:45 Therapeutic HPV Vaccination: The main discussion begins on a meta-analysis reviewing seven studies on the therapeutic use of the 9-valent HPV vaccine (Gardasil-9) in adult women who are already HPV-positive or have precancerous cervical lesions.
19:54 Key Findings on HPV Vaccine Efficacy: The analysis showed significant benefits for vaccination in this population. Key results include:
Complete disappearance of HPV was observed in 72% of vaccinated women versus 45% in unvaccinated women.
Vaccination was linked to reduced progression of squamous intraepithelial lesions (SIL).
Recurrence of high-grade lesions after surgical removal (conization) was significantly lower in vaccinated groups.
32:16 Cervical Lesion Progression (SIL/CIN): Rich Condit provides an overview of HPV pathology, explaining how the virus infects basal epithelial cells and can lead to a spectrum of conditions, from low-grade lesions (LSIL/CIN1) to high-grade lesions (HSIL/CIN2/3) and, potentially, invasive cervical cancer.
55:14 Practical Recommendations and Future Research: Based on the paper, the hosts discuss the recommendation to offer the HPV vaccine to HPV-positive women, especially before surgical procedures, to maximize benefits. They agree that more prospective, randomized clinical trials are needed to solidify these findings and create global guidelines.
59:28 Human Monoclonal Antibodies for Mpox: The second paper details the isolation of three potent human monoclonal antibodies (EV35-2, EV35-6, and EV35-7) from an mpox-convalescent individual. These antibodies target the A35 protein on the extracellular enveloped virion (EEV) form of the virus.
1:01:22 Poxvirus Infectious Forms (IMV vs. EEV): To provide context, Rich Condit explains the two forms of poxvirus particles. The intracellular mature virion (IMV) is responsible for transmission between hosts, while the extracellular enveloped virion (EEV) is crucial for spreading the virus from cell to cell within an infected individual. The A35 protein is on the EEV.
1:11:51 In Vivo Mouse Studies: The antibodies showed powerful protective effects in mice. When given prophylactically (before infection), they fully protected mice from death caused by vaccinia and mpox viruses. They also worked therapeutically, with high survival rates when administered 24 hours after infection.
1:23:31 Antibody Mechanisms of Action: The antibodies were found to inhibit viral spread, as shown in a "comet assay," and also utilize Fc-dependent mechanisms like complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). However, protection was still strong even when Fc functions were experimentally removed.
1:28:04 Structural Analysis Reveals a Key Target: Crystal structures showed that the antibodies bind to a highly conserved groove in the A35 protein dimer. This specific epitope is a promising target for developing pan-orthopoxvirus therapies and vaccines, as current vaccines do not appear to elicit a strong response to this site.
Reference Summaries
Endangered Research Monkey (ScienceInsider): The International Union for Conservation of Nature (IUCN) has reaffirmed the "endangered" status of long-tailed macaques, a common primate species used in biomedical research. This decision is supported by animal rights groups but raises concerns among scientists that it could lead to increased regulations and costs, potentially hindering drug development and other vital research.
Mosquitoes in Iceland (Science): For the first time, Iceland has recorded the presence of a breeding population of mosquitoes (Culiseta annulata). The discovery is linked to a warming climate and increased international transportation, highlighting how climate change is altering ecosystems and introducing new species to regions where they previously could not survive.
Impact of Vaccinating HPV-Positive Adult Women (Viruses): This systematic review analyzes seven studies involving over 19,000 women to evaluate the therapeutic effect of the 9-valent HPV vaccine. The findings show that vaccinating women who are already HPV-positive or have cervical lesions significantly reduces persistent infection, lowers the risk of lesion progression, and decreases recurrence after surgery, suggesting a strong benefit beyond prophylactic use.
Human Monoclonal Antibodies for Mpox (Cell): This study details the isolation and characterization of three potent human monoclonal antibodies from an mpox-convalescent individual that target the viral A35 protein. These antibodies protect mice from lethal infection, and structural analysis reveals they bind to a highly conserved epitope. The presence of similar antibodies in infected humans correlates with better clinical outcomes, establishing A35 as a promising target for mpox therapies.
Glossary of Technical Terms
ADCC (Antibody-Dependent Cell-Mediated Cytotoxicity): An immune mechanism where an antibody binds to a target cell (like a virus-infected cell), and then immune cells (like Natural Killer cells) recognize the antibody's Fc region and kill the target cell.
A35 Protein: A protein found on the surface of the extracellular enveloped virion (EEV) of orthopoxviruses, including mpox. It is a target for the immune system and the monoclonal antibodies discussed in the paper.
CIN (Cervical Intraepithelial Neoplasia): A precancerous condition in which abnormal cells grow on the surface of the cervix. It is graded from 1 (mild) to 3 (severe). It is largely synonymous with SIL.
Cohort Study: An observational study that follows a group of individuals (a cohort) over time to see how certain exposures (like a vaccine) affect outcomes (like disease recurrence).
Comet Assay: A laboratory technique used to visualize the cell-to-cell spread of poxviruses in a cell culture. An initial infection (the "head" of the comet) releases virus particles that create a trail of secondary infections (the "tail"). A therapy that inhibits spread will reduce or eliminate the tail.
EEV (Extracellular Enveloped Virion): One of the two infectious forms of poxvirus. It is wrapped in an extra membrane derived from the host cell and is crucial for spreading the virus between cells within an infected host.
Fc-dependent/independent mechanisms: Refers to how an antibody functions. Fc-dependent mechanisms rely on the "Fc region" (the antibody's tail) to interact with other parts of the immune system (like complement or immune cells). Fc-independent mechanisms involve the antibody directly blocking the virus, for example, by preventing it from entering a cell.
Gardasil-9: A vaccine that protects against nine types of Human Papillomavirus (HPV), including the seven types most commonly associated with cervical and other cancers, and two types that cause genital warts.
HPV (Human Papillomavirus): A group of more than 200 related viruses. Some types can cause warts, while high-risk types can cause cancers, most notably cervical cancer.
IMV (Intracellular Mature Virion): The most stable and abundant infectious form of poxvirus. It is primarily responsible for transmission from one host to another.
Meta-analysis: A statistical method that combines the results of multiple independent scientific studies to derive a conclusion that is statistically stronger than any single study.
Monoclonal Antibodies (mAbs): Laboratory-produced antibodies designed to recognize and bind to a specific target (an antigen), such as a particular protein on a virus. They can be used as therapeutic drugs.
Poxvirus: A family of large, complex DNA viruses that includes smallpox, mpox (monkeypox), and vaccinia virus.
SIL (Squamous Intraepithelial Lesion): A term used to describe abnormal, precancerous cell growth on the cervix caused by HPV. It can be low-grade (LSIL) or high-grade (HSIL).