Clinical Activity of Olvimulogene Nanivacirepvec-Primed Immunochemotherapy in Heavily Pretreated Patients With Platinum-Resistant or Platinum-Refractory Ovarian Cancer: The Nonrandomized Phase 2 VIRO-15 Clinical Trial.

Importance: Patients with platinum-resistant or platinum-refractory ovarian cancer (PRROC) have limited therapeutic options, representing a considerable unmet medical need. Objective: To assess antitumor activity and safety of intraperitoneal (IP) olvimulogene nanivacirepvec (Olvi-Vec) virotherapy and platinum-based chemotherapy with or without bevacizumab in patients with PRROC. Design, Setting, and Participants: This open-label, nonrandomized multisite phase 2 VIRO-15 clinical trial enrolled patients with PRROC with disease progression following their last prior line of therapy from September 2016 to September 2019. Data cutoff was on March 31, 2022, and data were analyzed between April 2022 and September 2022. Interventions: Olvi-Vec was administered via a temporary IP dialysis catheter as 2 consecutive daily doses (3 × 109 pfu/d) followed by platinum-doublet chemotherapy with or without bevacizumab. Main Outcomes and Measures: Primary outcomes were objective response rate (ORR) via Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) and cancer antigen 125 (CA-125) assay, and progression-free survival (PFS). Secondary outcomes included duration of response (DOR), disease control rate (DCR), safety, and overall survival (OS). Results: Twenty-seven heavily pretreated patients with platinum-resistant (n = 14) or platinum-refractory (n = 13) ovarian cancer were enrolled. The median (range) age was 62 (35-78) years. The median (range) prior lines of therapy were 4 (2-9). All patients completed both Olvi-Vec infusions and chemotherapy. Median follow-up duration was 47.0 months (95% CI, 35.9 months to NA). Overall, ORR by RECIST 1.1 was 54% (95% CI, 33%-74%), with a DOR of 7.6 months (95% CI, 3.7-9.6 months). The DCR was 88% (21/24). The ORR by CA-125 was 85% (95% CI, 65%-96%). Median PFS by RECIST 1.1 was 11.0 months (95% CI, 6.7-13.0 months), and the PFS 6-month rate was 77%. Median PFS was 10.0 months (95% CI, 6.4-NA months) in the platinum-resistant group and 11.4 months (95% CI, 4.3-13.2 months) in the platinum-refractory group. The median OS was 15.7 months (95% CI, 12.3-23.8 months) in all patients, with a median OS of 18.5 months (95% CI, 11.3-23.8 months) in the platinum-resistant group and 14.7 months (95% CI, 10.8-33.6 months) in the platinum-refractory group. Most frequent treatment-related adverse events (TRAEs) (any grade, grade 3) were pyrexia (63.0%, 3.7%, respectively) and abdominal pain (51.9%, 7.4%, respectively). There were no grade 4 TRAEs, and no treatment-related discontinuations or deaths. Conclusions and Relevance: In this phase 2 nonrandomized clinical trial, Olvi-Vec followed by platinum-based chemotherapy with or without bevacizumab as immunochemotherapy demonstrated promising ORR and PFS with a manageable safety profile in patients with PRROC. These hypothesis-generating results warrant further evaluation in a confirmatory phase 3 trial. Trial Registration: ClinicalTrials.gov Identifier: NCT02759588.

Short-term Adverse Events Following Immunization With Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) Vaccine for Mpox.

This study uses data collected by Australia's vaccine safety surveillance system to examine the adverse event profile of the modified vaccinia Ankara­Bavarian Nordic vaccine.

Hematopoietic stem cell donor vaccination with cytomegalovirus triplex augments frequencies of functional and durable cytomegalovirus-specific T cells in the recipient: A novel strategy to limit antiviral prophylaxis.

To enhance protective cytomegalovirus (CMV)-specific T cells in immunosuppressed recipients of an allogeneic hematopoietic cell transplant (HCT), we evaluated post-HCT impact of vaccinating healthy HCT donors with Triplex. Triplex is a viral vectored recombinant vaccine expressing three immunodominant CMV antigens. The vector is modified vaccinia Ankara (MVA), an attenuated, non-replicating poxvirus derived from the vaccinia virus strain Ankara. It demonstrated tolerability and immunogenicity in healthy adults and HCT recipients, in whom it also reduced CMV reactivation. Here, we report feasibility, safety, and immunological outcomes of a pilot phase 1 trial (NCT03560752 at ClinicalTrials.gov) including 17 CMV-seropositive recipients who received an HCT from a matched related donor (MRD) vaccinated with 5.1 × 108 pfu/ml of Triplex before cell harvest (median 15, range 11-28 days). Donor and recipient pairs who committed to participation in the trial resulted in exceptional adherence to the protocol. Triplex was well-tolerated with limited adverse events in donors and recipients, who all engrafted with full donor chimerism. On day 28 post-HCT, levels of functional vaccinia- and CMV-specific CD137+ CD8+ T cells were significantly higher (p < .0001 and p = .0174, respectively) in recipients of Triplex vaccinated MRD than unvaccinated MRD (control cohort). Predominantly, central and effector memory CMV-specific T-cell responses continued to steadily expand through 1-year follow-up. CMV viremia requiring antivirals developed in three recipients (18%). In summary, this novel approach represents a promising strategy applicable to different HCT settings for limiting the use of antiviral prophylaxis, which can impair and delay CMV-specific immunity, leading to CMV reactivation requiring treatment.

Smallpox Autoinoculation Via Tattoo in a Soldier.

Since the National Smallpox Vaccination Program began in 2002, over 2.4 million military servicemembers have been inoculated. Use of bifurcated needles to introduce live vaccinia virus by repeated skin trauma is largely the same process that was first developed over 200 years ago, and is similar to that of tattoo administration. Both tattoos and smallpox inoculation can cause local immune dysregulation, with prior research cautioning further complications if they are placed in the same area within a close timeframe. Here we present the case of a soldier with smallpox autoinoculation, who reported receiving a tattoo directly over his inoculation site 4 days after vaccination. Initial scattered flesh-colored papules evolved over several days to classic umbilicated lesions with additional fevers, chills, myalgias, and suspected secondary infection. Thirteen cases of tattoo and smallpox inoculation complications have been reported in the Vaccine Adverse Events Reporting System (VAERS) database in 15 years. Current US Army Public Health Command (USAPHC) guidance mandates no new tattoos for 30 days post-inoculation, although the Military Vaccine Agency notes that this period may be extended to a window of greater than 60 days on a case-by-case basis. This incident illustrates the risks of current smallpox vaccination practice and poor patient adherence to post-vaccination care instructions. Continued use of traditional smallpox vaccination administration necessitates increased education and emphasis on proper inoculation site aftercare.

Respiratory infection due to direct contact with rabbit-skin powder contaminated by vaccinia virus.

Vaccinia virus infection was diagnosed in five male workers directly exposed to rabbit-skin powder contaminated by vaccinia virus via skin contact and inhalation. Four of the workers had been vaccinated against smallpox. Their clinical symptoms were severe, especially in the lungs; however, all symptoms improved after treatment.

Smallpox vaccine complications: the dermatologist's role in diagnosis and management.

In 2002, the United States implemented a new program for smallpox vaccinations among military personnel using a live vaccinia virus product. Approximately 2.4 million US military service members and health care workers have since been inoculated, with considerable numbers experiencing adverse reactions. Military dermatologists are at the forefront of describing and treating these reactions, from relatively benign generalized vaccinia (GV) and erythema multiforme (EM) to more severe progressive vaccinia (PV) and eczema vaccinatum (EV). A wide range of providers, including civilian dermatologists and primary care providers, also may see such reactions and must be aware of the spectrum of vaccine reactions. Given current world instability (eg, threats of nuclear war, rise of authoritarian regimes) and concerns for bioterrorism attacks, the smallpox vaccine program likely will continue indefinitely. As the brisk military deployment tempo continues, a larger population of new vaccinees will yield more cutaneous reactions and diagnostic challenges.

Genital Autoinoculation with Vaccinia: A Look at Two Cases.

Introduction: Smallpox, or vaccinia, has been eradicated worldwide as a disease; however, it may be weaponized and is thus a required immunization when military members deploy to certain parts of the world. Materials and Methods: We report two unusual cases of genital autoinoculation following smallpox vaccination. Results: Both patients' lesions resolved without sequelae within 20 d. Conclusions: We advocate for thorough education on this potential vaccination adverse event. These cases highlight the importance of a broad differential diagnosis when dealing with vulvar lesions, particularly in our military population.

Concomitant helminth infection downmodulates the Vaccinia virus-specific immune response and potentiates virus-associated pathology.

The aim of this work was to elucidate the immunopathological mechanisms of how helminths may influence the course of a viral infection, using a murine model. Severe virulence, a relevant increase in the virus titres in the lung and a higher mortality rate were observed in Ascaris and Vaccinia virus (VACV) co-infected mice, compared with VACV mono-infected mice. Immunopathological analysis suggested that the ablation of CD8+ T cells, the marked reduction of circulating CD4+ T cells producing IFN-γ, and the robust pulmonary inflammation were associated with the increase of morbidity/mortality in co-infection and subsequently with the negative impact of concomitant pulmonary ascariasis and respiratory VACV infection for the host. On the other hand, when evaluating the impact of the co-infection on the parasitic burden, co-infected mice presented a marked decrease in the total number of migrating Ascaris lung-stage larvae in comparison with Ascaris mono-infection. Taken together, our major findings suggest that Ascaris and VACV co-infection may potentiate the virus-associated pathology by the downmodulation of the VACV-specific immune response. Moreover, this study provides new evidence of how helminth parasites may influence the course of a coincident viral infection.

[Methods and Means for Defense from Collateral Action of Vaccine Virus after Vaccination Against Spallpox].

In connection with actuality of smallpox vaccination at present its methods and means are discussed to increase the safety of the first immunization with live vaccines.

Spread of vaccinia virus through shaving during military training, Joint Base San Antonio-Lackland, TX, June 2014.

Although naturally occurring smallpox virus was officially declared eradicated in 1980, concern for biological warfare prompted the U.S. Government in 2002 to recommend smallpox vaccination for select individuals. Vaccinia, the smallpox vaccine virus, is administered into the skin, typically on the upper arm, where the virus remains viable and infectious until the scab falls off and the epidermis is fully intact - typically 2-4 weeks. Adverse events following smallpox vaccination may occur in the vaccinee, in individuals who have contact with the vaccinee (i.e., secondary transmission), or in individuals who have contact with the vaccinee's contact (i.e., tertiary transmission). In June 2014 at Joint Base San Antonio-Lackland, TX, two cases of inadvertent inoculation of vaccinia and one case of a non-viral reaction following vaccination occurred in the security forces training squadron. This includes the first reported case of shaving as the likely source of autoinoculation after contact transmission. This paper describes the diagnosis and treatment of these cases, the outbreak investigation, and steps taken to prevent future transmission.

[Analysis on status and characteristics of laboratory-acquired vaccinia virus infections cases].

OBJECTIVE: By analyzing the status and characteristics of vaccinia virus laboratory-acquired infections in the bibliographical information, this paper provides relevant recommendations and measures for prevention and control of vaccinia virus laboratory-acquired infections in China. METHODS: Choosing PubMed, Embase, Biosis and SCIE, SSCI, CPCI-S as well as CPCI-SSH covered by Web of Science as the data source, indexing the bibliography of vaccinia virus laboratory-acquired infections, this paper analyzes the information on whether to vaccinate, the occurrence time of symptoms, diseasedparts, symptom characteristics and the disease-causing reasons. RESULTS: The outcome shows that 52. 9% of the cases never get vaccinated, 82.4% engaged in vaccinia virus related researches never get vaccinated in 10 years, 52. 9% get infected by the accidental needlestick in hands during the process of handling animal experiments, 70. 6% of infections occur in the hands and having symptoms after being exposed with an average of 5. 1 days. CONCLUSION: Although it is still controversial that whether or not to be vaccinated before carrying out vaccinia virus related works, it should be important aspects of prevention and control of vaccinia virus laboratory-acquired infections with the strict compliance with the operating requirements of the biosafety, by strengthening personal protection and timely taking emergency measures when unforeseen circumstances occur, as well as providing the research background information to doctors.

Working safely with vaccinia virus: laboratory technique and review of published cases of accidental laboratory infections.

Vaccinia virus (VACV), the prototype orthopoxvirus, is widely used in the laboratory as a model system to study various aspects of viral biology and virus-host interactions, as a protein expression system, as a vaccine vector, and as an oncolytic agent. The ubiquitous use of VACVs in the laboratory raises certain safety concerns because the virus can be a pathogen in individuals with immunological and dermatological abnormalities, and on occasion can cause serious problems in normal hosts. This chapter reviews standard operating procedures when working with VACV and reviews published cases on accidental laboratory infections.

Introduction of the six major genomic deletions of modified vaccinia virus Ankara (MVA) into the parental vaccinia virus is not sufficient to reproduce an MVA-like phenotype in cell culture and in mice.

Modified vaccinia virus Ankara (MVA) has a highly restricted host range in cell culture and is apathogenic in vivo. MVA was derived from the parental chorioallantois vaccinia virus Ankara (CVA) by more than 570 passages in chicken embryo fibroblast (CEF) cells. During CEF cell passaging, six major deletions comprising 24,668 nucleotides occurred in the CVA genome. We have cloned both the MVA and the parental CVA genome as bacterial artificial chromosomes (BACs) and have sequentially introduced the six major MVA deletions into the cloned CVA genome. Reconstituted mutant CVA viruses containing up to six major MVA deletions showed no detectable replication restriction in 12 of 14 mammalian cell lines tested; the exceptions were rabbit cell lines RK13 and SIRC. In mice, CVA mutants with up to three deletions showed slightly enhanced virulence, suggesting that gene deletion in replicating vaccinia virus (VACV) can result in gain of fitness in vivo. CVA mutants containing five or all six deletions were still pathogenic, with a moderate degree of attenuation. Deletion V was mainly responsible for the attenuated phenotype of these mutants. In conclusion, loss or truncation of all 31 open reading frames in the six major deletions is not sufficient to reproduce the specific MVA phenotype of strong attenuation and highly restricted host range. Mutations in viral genes outside or in association with the six major deletions appear to contribute significantly to this phenotype. Host range restriction and avirulence of MVA are most likely a cooperative effect of gene deletions and mutations involving the major deletions.

Progressive vaccinia in a military smallpox vaccinee - United States, 2009.

Progressive vaccinia (PV), previously known as vaccinia necrosum, vaccinia gangrenosum, or disseminated vaccinia, is a rare, often fatal adverse event after vaccination with smallpox vaccine, which is made from live vaccinia virus. During recent vaccination programs potential cases of PV were investigated, but none met standard case definitions. PV has not been confirmed to have occurred in the United States since 1987. On March 2, 2009, a U.S. Navy Hospital contacted the Poxvirus Program at CDC to report a possible case of PV in a male military smallpox vaccinee. The service member had been newly diagnosed with acute mylegenous leukemia M0 (AML M0). During evaluation for a chemotherapy-induced neutropenic fever, he was found to have an expanding and nonhealing painless vaccination site 6.5 weeks after receipt of smallpox vaccine. Clinical and laboratory investigation confirmed that the vaccinee met the Brighton Collaboration and CDC adverse event surveillance guideline case definition for PV. This report summarizes the patient's protracted clinical course and the military and civilian interagency governmental, academic, and industry public health contributions to his complex medical management. The quantities of investigational and licensed therapeutics and diagnostics used were greater than anticipated based on existing smallpox preparedness plans. To support future public health needs adequately, the estimated national supply of therapeutics and diagnostic resources required to care for smallpox vaccine adverse events should be reevaluated.

Vulvar vaccinia infection after sexual contact with a smallpox vaccinee.

Vaccinia (smallpox) vaccine is an effective immunizing agent that brought about global eradication of naturally occurring smallpox, as declared by the World Health Organization in 1980. The United States ceased generalized smallpox vaccination in 1972 but reinstated it in 2002 for military personnel and selected healthcare workers (first responders who may be investigating possible cases of smallpox or caring for patients in selected hospitals) after the 2001 bioterrorism attacks. Since reinstitution of the vaccine, reports of transmission of vaccinia virus through contact with military smallpox vaccinees have been published, including four cases of female genital infection. We report a subsequent case of vulvar vaccinia infection acquired during sexual contact with a military vaccinee.