Equivalence of freeze-dried and liquid-frozen formulations of MVA-BN as smallpox and mpox vaccine.

Modified Vaccinia Ankara Bavarian Nordic (MVA-BN) as a smallpox and mpox vaccine has been approved in its liquid-frozen (LF) formulation in the US, Canada, and EU. A freeze-dried (FD) formulation may offer additional benefits, such as a longer shelf life and reduced dependence on cold chain storage and transport. In a phase 2 clinical trial, 651 vaccinia-naïve participants were vaccinated with two doses of MVA-BN LF or FD, 4 weeks apart. The objectives were to compare MVA-BN FD with LF in terms of vaccine-induced immune responses, safety, and reactogenicity. Non-inferiority of the immune response was assessed by the 95% CI of the geometric mean ratios. Both formulations induced robust vaccinia-specific humoral and cellular immune responses. At peak humoral responses (Week 6), geometric means of total antibody titers were 1096 (95% CI 1013, 1186) from the FD group and 877 (95% CI 804, 956) from the LF group, achieving the primary endpoint of non-inferiority of MVA-BN FD compared to MVA-BN LF. At peak cellular responses (Week 2), geometric means of T cell spot forming units were 449 (95% CI 341, 590) from the FD group and 316 (95% CI 234, 427) from the LF group. Both formulations of MVA-BN were well tolerated, with similar unsolicited AEs and solicited systemic reactions in both groups but slightly more local reactions in the FD group. No vaccine-related serious adverse events (SAEs) or vaccine-related AE of special interest were reported. The FD formulation of MVA-BN was shown to be equivalent to MVA-BN LF.

Real-world safety data for MVA-BN: Increased frequency of syncope following intradermal administration for immunization against mpox disease.

BACKGROUND: MVA-BN vaccine (Jynneos, Imvamune, Imvanex) was used widely in the 2022 mpox outbreak. This experience provides real-world evidence about the vaccine's safety, particularly regarding intradermal use. METHODS: Bavarian Nordic's global safety database was searched for all adverse events following immunization (AEFIs) with MVA-BN. AEFI numbers were compared among administration routes. Selected events and administered doses were graphed over the mpox outbreak period. RESULTS: A total of 9585 AEFIs have been reported. The rate of myocarditis or pericarditis was <1 per 100,000 doses administered. Eighty-nine cases of syncope, fainting, or loss of consciousness were reported. This number rose after the August 2022 US emergency use authorization for intradermal administration, as did the proportion of all syncope AEFIs reported following intradermal administration (78,7 %). CONCLUSION: Real-world data from large-scale administration of MVA-BN has confirmed the vaccine's established safety profile when administered subcutaneously. Intradermal administration is likely associated with increased syncopal event frequency.

Safety and immunogenicity of a novel trivalent recombinant MVA-based equine encephalitis virus vaccine: A Phase 1 clinical trial.

BACKGROUND: Three encephalitic alphaviruses-western, eastern, and Venezuelan equine encephalitis virus (WEEV, EEEV and VEEV)-can cause severe disease and have the potential to be used as biological weapons. There are no approved vaccines for human use. A novel multivalent MVA-BN-WEV vaccine encodes the envelope surface proteins of the 3 viruses and is thereby potentially able to protect against them all, as previously demonstrated in animal models. This first-in-human study assessed the safety, tolerability, and immunogenicity of MVA-BN-WEV vaccine in healthy adult participants. METHODS: Forty-five participants were enrolled into 3 dose groups (1 × 10E7 Inf.U, 1 × 10E8 Inf.U, and 2 × 10E8 Inf.U), received 2 doses 4 weeks apart, and were then monitored for 6 months. RESULTS: The safety profile of MVA-BN-WEV was acceptable at all administered doses, with incidence of local solicited AEs increased with increasing dose and no other clinically meaningful differences between dose groups. One SAE (Grade 2 pleural effusion) was reported in the lowest dose group and assessed as possibly related. No AEs resulted in death or led to withdrawal from the second vaccination or from the trial. The most common local solicited AE was injection site pain, and general solicited AEs were headache, fatigue, and myalgia. MVA-BN-WEV induced humoral immune responses; WEEV-, EEEV- and VEEV-specific neutralizing antibody responses peaked 2 weeks following the second vaccination, and the magnitude of these responses increased with dose escalation. The highest dose resulted in seroconversion of all (100 %) participants for WEEV and VEEV and 92.9 % for EEEV, 2 weeks following second vaccination, and durability was observed for 6 months. MVA-BN-WEV induced cellular immune responses to VEEV E1 and E2 (EEEV and WEEV not tested) and a dose effect for peptide pool E2. CONCLUSION: The study demonstrated that MVA-BN-WEV is well tolerated, induces immune responses, and is suitable for further development. CLINICAL TRIAL REGISTRY NUMBER: NCT04131595.

A randomized phase 3 trial to assess the immunogenicity and safety of 3 consecutively produced lots of freeze-dried MVA-BN® vaccine in healthy adults.

Since vaccination remains the only effective protection against orthopox virus-induced diseases such as smallpox or monkeypox, the strategic use and stockpiling of these vaccines remains of significant public health importance. The approved liquid-frozen formulation of Bavarian Nordic's Modified Vaccinia Ankara (MVA-BN) smallpox vaccine has specific cold-chain requirements, while the freeze-dried (FD) formulation of this vaccine provides more flexibility in terms of storage conditions and shelf life. In this randomized phase 3 trial, the immunogenicity and safety of 3 consecutively manufactured lots of the FD MVA-BN vaccine was evaluated. A total of 1129 healthy adults were randomized to 3 treatment groups (lots 1 to 3) and received 2 vaccinations 4 weeks apart. For both neutralizing and total antibodies, a robust increase of geometric mean titer (GMT) was observed across all lot groups 2 weeks following the second vaccination, comparable to published data. For the primary results, the ratios of the neutralizing antibody GMTs between the lot group pairs ranged from 0.936 to 1.115, with confidence ratios well within the pre-specified margin of equivalence. Results for total antibodies were similar. In addition, seroconversion rates were high across the 3 lots, ranging between 99.1 % and 99.7 %. No safety concerns were identified; particularly, no inflammatory cardiac disorders were detected. The most common local solicited adverse events (AEs) reported across lot groups were injection site pain (87.2%) and erythema (73.2%), while the most common general solicited adverse events were myalgia, fatigue, and headache in 40.6% to 45.5% of all participants, with no meaningful differences among the lot groups. No related serious AEs were reported. In conclusion, the data demonstrate consistent and robust immunogenicity and safety results with a freeze-dried formulation of MVA-BN. Clinical Trial Registry Number: NCT03699124.

Broad Antibody and Cellular Immune Response From a Phase 2 Clinical Trial With a Novel Multivalent Poxvirus-Based Respiratory Syncytial Virus Vaccine.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in young children and the elderly. Protective immunity is not generated after repeated infections, but vaccination may hopefully prove effective. METHODS: This phase 2 clinical study investigated a multivalent RSV vaccine (MVA-BN-RSV) designed to induce broad antibody and cellular immune responses by encoding RSV surface proteins F, G (for both A and B subtypes), and internal antigens (M2, N). This study evaluated the immune response in adults aged ≥55 years to identify the optimal MVA-BN-RSV dose and vaccination schedule. RESULTS: A single dose increased the levels of neutralizing (plaque reduction neutralization test to RSV A and B) and total (IgG and IgA ELISA) antibodies (1.6 to 3.4-fold increase from baseline) and induced a broad Th1-biased cellular immune response (interferon-γ ELISPOT) to all 5 vaccine inserts (5.4 to 9.7-fold increases). Antibody responses remained above baseline for 6 months. A 12-month booster dose elicited a booster effect in antibody and T-cell responses (up to 2.8-fold from preboost levels). No drug-related serious adverse events were reported. CONCLUSIONS: MVA-BN-RSV induces a broad immune response that persists at least 6 months and can be boosted at 12 months, without significant safety findings. CLINICAL TRIALS REGISTRATION: NCT02873286.

Safety and immunogenicity of novel modified vaccinia Ankara-vectored RSV vaccine: A randomized phase I clinical trial.

Respiratory disease caused by RSV infection is recognized as a severe public health issue in infants, young children and elderly with no specific treatment option. Vaccination may be the most effective strategy to combat this highly infectious virus although no vaccine has been approved. The novel vaccine candidate MVA-BN-RSV encodes RSV surface proteins F and G (subtypes A, B) as well as internal proteins N and M2 in the MVA-BN viral vector backbone to provide broad protection against RSV. This was a first in human study to investigate safety, reactogenicity and immunogenicity of MVA-BN-RSV. Sixty-three participants were allocated to 3 groups: adult (18-49 years) low (1 × 107 TCID50) or high (1 × 108 TCID50) dose and older adult (50-65 years) high dose. Participants in each group were randomized in a 6:1 ratio to receive 2 doses of MVA-BN-RSV or placebo 4 weeks apart and were monitored for 30 weeks. All participants completed the study, receiving both doses. No serious AEs or AEs of special interest were reported. The most common AEs were injection site pain (56% in the combined high dose groups, 17% in the low dose group). MVA-BN-RSV induced robust T cell responses covering all 5 inserts with fold increases ranging from 1.8 to 3.8. Higher and broader responses were observed in the high dose groups (83% responders to at least 3 peptide pools in the combined high dose groups compared to 63% in the low dose group). Moderate but consistent humoral responses were observed against A and B RSV subtypes (up to approximately 2-fold increases in the high dose groups). No differences were observed between the adult and the older adult groups in safety, reactogenicity or immunogenicity. The study demonstrated that the well tolerated MVA-BN-RSV vaccine candidate induces broad cellular and humoral immune responses, warranting further development.

Overexpression of PTK6 (breast tumor kinase) protein--a prognostic factor for long-term breast cancer survival--is not due to gene amplification.

In a previous retrospective study, we demonstrated the prognostic value of protein tyrosine kinase 6 (PTK6) protein expression in breast carcinomas. Here, we analyzed PTK6 gene amplification using fluorescence in situ hybridization technique in a cohort of 426 invasive breast carcinomas and compared it with PTK6 expression level as well as with the clinical outcome of patients. Forty-five percent of tumors show increased PTK6 gene copy numbers when compared to normal tissue. Most of these, however, were related to chromosome 20 polysomy (30%), while gene amplification accounted for only 15%. Only "low level" amplification of the PTK6 gene, with up to eight signals per nucleus, was found. The PTK6 cytogenetic status (normal, gene amplification, polysomy 20) was not associated with histopathological parameters or with the protein expression of HER receptors. No statistical association was identified between PTK6 gene status and expression level. Further, the PTK6 gene status does not influence the disease-free survival of patients at > or = 240 months. Based on these results, we state that the PTK6 overexpression is not essentially attributed to gene amplification, and the PTK6 protein expression-but not gene status-is of prognostic value in breast carcinomas. PTK6 protein overexpression may result from polysomy 20 in a minority of the tumors. In a marked proportion of tumors, however, the overexpression is likely to be caused by posttranscriptional regulation mechanisms.