Mv130 Vaccine

[Giorgio Aguilar]

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MV130 is an inactivated polybacterial mucosal vaccine that confers protection to patients against recurrent respiratory infections, including those of viral etiology. However, its mechanism of action remains poorly understood. Here, we find that intranasal prophylaxis with MV130 modulates the lung immune landscape and provides long-term heterologous protection against viral respiratory infections in mice. Intranasal administration of MV130 provides protection against systemic candidiasis in wild-type and Rag1-deficient mice lacking functional lymphocytes, indicative of innate immune-mediated protection. Moreover, pharmacological inhibition of trained immunity with metformin abrogates the protection conferred by MV130 against influenza A virus respiratory infection. MV130 induces reprogramming of both mouse bone marrow progenitor cells and in vitro human monocytes, promoting an enhanced cytokine production that relies on a metabolic shift. Our results unveil that the mucosal administration of a fully inactivated bacterial vaccine provides protection against viral infections by a mechanism associated with the induction of trained immunity.

COVID-19-specific vaccines are efficient prophylactic weapons against SARS-CoV-2 virus. However, boosting innate responses may represent an innovative way to immediately fight future emerging viral infections or boost vaccines. MV130 is a mucosal immunotherapy, based on a mixture of whole heat-inactivated bacteria, that has shown clinical efficacy against recurrent viral respiratory infections. Herein, we show that the prophylactic intranasal administration of this immunotherapy confers heterologous protection against SARS-CoV-2 infection in susceptible K18-hACE2 mice. Furthermore, in C57BL/6 mice, prophylactic administration of MV130 improves the immunogenicity of two different COVID-19 vaccine formulations targeting the SARS-CoV-2 spike (S) protein, inoculated either intramuscularly or intranasally. Independently of the vaccine candidate and vaccination route used, intranasal prophylaxis with MV130 boosted S-specific responses, including CD8+-T cell activation and the production of S-specific mucosal IgA antibodies. Therefore, the bacterial mucosal immunotherapy MV130 protects against SARS-CoV-2 infection and improves COVID-19 vaccines immunogenicity.

Copyright 2021 del Fresno, Garca-Arriaza, Martnez-Cano, Heras-Murillo, Jarit-Cabanillas, Amores-Iniesta, Brandi, Dunphy, Suay-Corredera, Pricolo, Vicente, Lpez-Perrote, Cabezudo, Gonzlez-Corpas, Llorca, Alegre-Cebollada, Garaigorta, Gastaminza, Esteban and Sancho. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

The results demonstrate the ability of MV130 to protect against viral infections (influenza and vaccinia viruses), confirming recent results with MV130 against SARS-CoV-2. This study also demonstrates that this protection depends on the ability of MV130 to induce Trained Immunity. This type of immunity is long-lasting (it generates memory) and depends on epigenetic and metabolic changes that increase the responsiveness of the cells of the Innate Immune System. This confers greater protection against different infections, including viral infections.

MV130 is an inactivated bacterial preparation developed by INMUNOTEK that meets the criteria for trained immunity-based vaccines (TIbV) and has proven clinical efficacy in preventing viral infections such as those that cause bronchiolitis in children.

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While the company is based in Spain, Inmunotek has sales offices and subsidiaries in Portugal and in the Spanish-speaking countries of Latin America, and has distribution and contract manufacturing partnerships around the world.

One of the advantages of using mucosal rather than parenteral vaccines for infections in the respiratory and urinary tract is that they stimulate the mucosal immune system, which is the primary first defense against these types of infection.

MV130 has completed a phase 3, double-blind, placebo-controlled clinical trial for the prevention of recurrent wheezing in children, a condition mainly caused by viral infections, such as rhinoviruses. There are no specific vaccines currently available for these viral infections.

The same vaccine is currently in a double-blind, placebo-controlled phase 3 efficacy and safety study in patients with chronic obstructive pulmonary disease (COPD), with an aim to reduce the number of COPD exacerbations. This study is due to be completed in 2019.

Inmunotek believes that broadly active vaccines that target trained immunity may be a valuable alternative when conventional vaccines are not available or when a number of different microorganisms cause co-infections.

Today, the U.S. Food and Drug Administration approved Abrysvo (Respiratory Syncytial Virus Vaccine), the first vaccine approved for use in pregnant individuals to prevent lower respiratory tract disease (LRTD) and severe LRTD caused by respiratory syncytial virus (RSV) in infants from birth through 6 months of age. Abrysvo is approved for use at 32 through 36 weeks gestational age of pregnancy. Abrysvo is administered as a single dose injection into the muscle. The FDA approved Abrysvo in May for the prevention of LRTD caused by RSV in individuals 60 years of age and older.

RSV is a highly contagious virus that causes respiratory infections in individuals of all age groups. It is the most frequent cause of lower respiratory tract illness in infants worldwide. In most parts of the U.S., RSV circulation is seasonal, typically starting during the fall and peaking in the winter. The virus is especially common in children, and most individuals can be expected to be infected with RSV by the time they reach two years of age. While RSV most often causes cold-like symptoms in infants and young children, it can also lead to serious LRTD such as pneumonia and bronchiolitis (swelling of the small airway passages in the lungs). In infants and children, the risk of RSV-associated LRTD is highest during the first year of life. According to the Centers for Disease Control and Prevention, RSV is the leading cause of infant hospitalization in the U.S.

The safety and effectiveness of Abrysvo for immunization of pregnant individuals to prevent LRTD and severe LRTD caused by RSV in infants from birth through 6 months of age was evaluated in ongoing, randomized, placebo-controlled international clinical studies.

A clinical study evaluated the effectiveness of Abrysvo to prevent LRTD and severe LRTD caused by RSV in infants born to individuals who were vaccinated during pregnancy. Among approximately 3,500 pregnant individuals who received Abrysvo, compared to approximately 3,500 pregnant individuals who received placebo, Abrysvo reduced the risk of severe LRTD by 81.8% within 90 days after birth, and 69.4% within 180 days after birth. In a subgroup of pregnant individuals who were 32 through 36 weeks gestational age, of whom approximately 1,500 received Abrysvo and 1,500 received placebo, Abrysvo reduced the risk of LRTD by 34.7%, and reduced the risk of severe LRTD by 91.1% within 90 days after birth when compared to placebo. Within 180 days after birth, Abrysvo reduced the risk of LRTD by 57.3% and by 76.5% for severe LRTD, when compared to placebo.

The safety of Abrysvo was evaluated in two studies. In one study, approximately 3,600 pregnant individuals received a single dose of Abrysvo and approximately 3,600 pregnant individuals received a placebo. In the second study, approximately 100 pregnant individuals received Abrysvo and approximately 100 pregnant individuals received placebo.

In addition, although not commonly reported, a dangerous hypertensive disorder, known as pre-eclampsia, occurred in 1.8% of pregnant individuals who received Abrysvo compared to 1.4% of pregnant individuals who received placebo. In the safety studies, low birth weight and jaundice in infants occurred at a higher rate in the pregnant Abrysvo recipients compared to pregnant placebo recipients.

The Prescribing Information for Abrysvo includes a warning to inform that a numerical imbalance in preterm births in Abrysvo recipients (5.7%) occurred compared to those who received placebo (4.7%). The available data are insufficient to establish or exclude a causal relationship between preterm birth and Abrysvo. Specifically, the warning informs healthcare providers that to avoid the potential risk of preterm birth with use of Abrysvo before 32 weeks of gestation, administer Abrysvo as indicated in pregnant individuals at 32 through 36 weeks gestational age. Pregnant individuals who were at increased risk of preterm birth were generally excluded from clinical studies of Abrysvo.

Effect of trained immunity on ongoing immune responses. Induction of trained immunity allows trained cells to enhance adaptive immune responses and vice versa, final effector functions of trained cells can be further potentiated by enhanced adaptive responses.

Different possibilities of trained immunity-based vaccines (TIbVs). Under the umbrella of trained immunity-based vaccines (TIbVs) different possibilities exist depending on their design and purpose. Bona fide TIbVs are those containing both trained immunity inducers and antigens in the same vaccine as occurs in conventional vaccines with trained immunity inducing properties. These vaccines show heterologous protection in addition to the specific response to the target antigen. TIbIs are intended just to confer non-specific protection by means of trained immunity induction beyond the intrinsic antigens they may contain. TIbAs are intended to enhance the specific response of other vaccines that are administered later, once trained immunity has been induced, or specific antigens combined in the same vaccine as any other adjuvant.

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