Adenoviral-vectored universal influenza vaccines administered intranasally reduce lung inflammatory responses upon viral challenge 15 months post-vaccination.

Vaccines targeting highly conserved proteins can protect broadly against diverse viral strains. When a vaccine is administered to the respiratory tract, protection against disease is especially powerful. However, it is important to establish that this approach is safe.

Reduction of Influenza A Virus Transmission in Mice by a Universal Intranasal Vaccine Candidate is Long-Lasting and Does Not Require Antibodies.

Vaccination against influenza virus infection can protect the vaccinee and also reduce transmission to contacts. Not all types of vaccines induce sterilizing immunity via neutralizing antibodies; some instead permit low-level, transient infection. There has been concern that infection-permissive influenza vaccines may allow continued spread in the community despite minimizing symptoms in the vaccinee.

Universal influenza vaccine based on conserved antigens provides long-term durability of immune responses and durable broad protection against diverse challenge virus strains in mice.

Current influenza vaccines rely on inducing antibody responses to the rapidly evolving hemagglutinin (HA) and neuraminidase (NA) proteins, and thus need to be strain-matched. However, predictions of strains that will circulate are imperfect, and manufacturing of new vaccines based on them takes months. As an alternative, universal influenza vaccines target highly conserved antigens.

Effect of an Adenovirus-Vectored Universal Influenza Virus Vaccine on Pulmonary Pathophysiology in a Mouse Model.

Current influenza vaccines, live attenuated or inactivated, do not protect against antigenically novel influenza A viruses (IAVs) of pandemic potential, which has driven interest in the development of universal influenza vaccines. Universal influenza vaccine candidates targeting highly conserved antigens of IAV nucleoprotein (NP) are promising as vaccines that induce T cell immunity, but concerns have been raised about the safety of inducing robust CD8 T cell responses in the lungs. Using a mouse model, we systematically evaluated effects of recombinant adenovirus vectors (rAd) expressing IAV NP (A/NP-rAd) or influenza B virus (IBV) NP (B/NP-rAd) on pulmonary inflammation and function after vaccination and following live IAV challenge.

Beyond clinical trials: Evolutionary and epidemiological considerations for development of a universal influenza vaccine.

The prospect of universal influenza vaccines is generating much interest and research at the intersection of immunology, epidemiology, and viral evolution. While the current focus is on developing a vaccine that elicits a broadly cross-reactive immune response in clinical trials, there are important downstream questions about global deployment of a universal influenza vaccine that should be explored to minimize unintended consequences and maximize benefits. Here, we review and synthesize the questions most relevant to predicting the population benefits of universal influenza vaccines and discuss how existing information could be mined to begin to address these questions.

The effect of respiratory viruses on immunogenicity and protection induced by a candidate universal influenza vaccine in mice.

Current approaches to influenza control rely on vaccines matched to viruses in circulation. Universal influenza vaccines would offer the advantage of providing broad protection against diverse strains of influenza virus. Candidate universal vaccines are developed using model systems, often testing in naïve animals.

Universal Influenza Vaccines: Progress in Achieving Broad Cross-Protection In Vivo.

Despite all we have learned since 1918 about influenza virus and immunity, available influenza vaccines remain inadequate to control outbreaks of unexpected strains. Universal vaccines not requiring strain matching would be a major improvement. Their composition would be independent of predicting circulating viruses and thus potentially effective against unexpected drift or pandemic strains.

Reduction of influenza virus transmission from mice immunized against conserved viral antigens is influenced by route of immunization and choice of vaccine antigen.

Transmission of influenza virus between susceptible hosts mediates spread of infection in the population and can occur via direct-contact or airborne routes. Mathematical models suggest that vaccines that reduce viral transmission from infected individuals could substantially reduce viral spread in an epidemic or pandemic, even if they do not completely protect against infection. Vaccines targeting conserved nucleoprotein (A/NP) and matrix 2 (M2) antigens of influenza virus do not completely prevent infection upon influenza virus challenge, but reduce viral replication, morbidity, and mortality.

Conventional influenza vaccines influence the performance of a universal influenza vaccine in mice.

Universal influenza vaccines are designed to protect against diverse strains of influenza virus. Preclinical testing of new vaccine candidates is usually done in naïve animals, despite intended use in the human population with its varied immune history including responses to previous vaccinations. As an approach more relevant to human use, we tested a candidate universal influenza vaccine in mice with a history of conventional vaccination.

Surveillance Study of Influenza Occurrence and Immunity in a Wisconsin Cohort During the 2009 Pandemic.

Background: Antibody and T-cell immunity to conserved influenza virus antigens can protect animals against infection with diverse influenza strains. Although immunity against conserved antigens occurs in humans, whether such responses provide cross-protection in humans and could be harnessed as the basis for universal influenza vaccines is controversial. The 2009 pandemic provided an opportunity to investigate whether pre-existing cross-reactive immunity affected susceptibility to infection.

Age Dependence of Immunity Induced by a Candidate Universal Influenza Vaccine in Mice.

Influenza has a major impact on the elderly due to increased susceptibility to infection with age and poor response to current vaccines. We have studied universal influenza vaccine candidates based on influenza A nucleoprotein and matrix 2 (A/NP+M2). Long-lasting protection against influenza virus strains of divergent subtypes is induced, especially with mucosal immunization.

Mucosal immunization with a candidate universal influenza vaccine reduces virus transmission in a mouse model.

Unlabelled: Pandemic influenza is a major public health concern, but conventional strain-matched vaccines are unavailable early in a pandemic. Candidate "universal" vaccines targeting the viral antigens nucleoprotein (NP) and matrix 2 (M2), which are conserved among all influenza A virus strains and subtypes, could be manufactured in advance for use at the onset of a pandemic. These vaccines do not prevent infection but can reduce disease severity, deaths, and virus titers in the respiratory tract.

Continuing to strengthen FDA's science approach to emerging technologies.

Emerging technologies result when advances and innovation in technology lead to discoveries. Often emerging technologies stimulate novel research in medical product development that contribute to new approaches to manufacturing and can improve the quality of products. By supporting investments in agency coordination, staff training and professional development, regulatory science research, stakeholder engagement, and enhancing opportunities for expert input, the U.

Vaccination to conserved influenza antigens in mice using a novel Simian adenovirus vector, PanAd3, derived from the bonobo Pan paniscus.

Among approximately 1000 adenoviruses from chimpanzees and bonobos studied recently, the Pan Adenovirus type 3 (PanAd3, isolated from a bonobo, Pan paniscus) has one of the best profiles for a vaccine vector, combining potent transgene immunogenicity with minimal pre-existing immunity in the human population. In this study, we inserted into a replication defective PanAd3 a transgene expressing a fusion protein of conserved influenza antigens nucleoprotein (NP) and matrix 1 (M1). We then studied antibody and T cell responses as well as protection from challenge infection in a mouse model.

Impact of cross-protective vaccines on epidemiological and evolutionary dynamics of influenza.

Large-scale immunization has profoundly impacted control of many infectious diseases such as measles and smallpox because of the ability of vaccination campaigns to maintain long-term herd immunity and, hence, indirect protection of the unvaccinated. In the case of human influenza, such potential benefits of mass vaccination have so far proved elusive. The central difficulty is a considerable viral capacity for immune escape; new pandemic variants, as well as viral escape mutants in seasonal influenza, compromise the buildup of herd immunity from natural infection or deployment of current vaccines.

Intranasal administration of adeno-associated virus type 12 (AAV12) leads to transduction of the nasal epithelia and can initiate transgene-specific immune response.

A critical aspect in defining the utility of a vector for gene therapy applications is the cell tropism and biodistribution of the vector. Adeno-associated virus type 12 (AAV12) has several unique biological and immunological properties that could be exploited for gene therapy purposes, including a unique cell surface receptor, transduction of epithelial cells, and limited neutralization by pooled human antibodies. However, little is known about its cell tropism and biodistribution in vivo.

Cold-adapted influenza and recombinant adenovirus vaccines induce cross-protective immunity against pH1N1 challenge in mice.

Background: The rapid spread of the 2009 H1N1 pandemic influenza virus (pH1N1) highlighted problems associated with relying on strain-matched vaccines. A lengthy process of strain identification, manufacture, and testing is required for current strain-matched vaccines and delays vaccine availability. Vaccines inducing immunity to conserved viral proteins could be manufactured and tested in advance and provide cross-protection against novel influenza viruses until strain-matched vaccines became available.

TLR3-specific double-stranded RNA oligonucleotide adjuvants induce dendritic cell cross-presentation, CTL responses, and antiviral protection.

Maturation of dendritic cells (DC) to competent APC is essential for the generation of acquired immunity and is a major function of adjuvants. dsRNA, a molecular signature of viral infection, drives DC maturation by activating TLR3, but the size of dsRNA required to activate DC and the expression patterns of TLR3 protein in DC subsets have not been established. In this article, we show that cross-priming CD8α(+) and CD103(+) DC subsets express much greater levels of TLR3 than other DC.

Cross-protective immunity to influenza A viruses.

Antigenic changes in influenza virus occur gradually, owing to mutations (antigenic drift), and abruptly, owing to reassortment among subtypes (antigenic shift). Availability of strain-matched vaccines often lags behind these changes, resulting in a shortfall in public health. In animal models, cross-protection by vaccines based on conserved antigens does not completely prevent infection, but greatly reduces morbidity, mortality, virus replication and, thus, viral shedding and spread.

Single-dose mucosal immunization with a candidate universal influenza vaccine provides rapid protection from virulent H5N1, H3N2 and H1N1 viruses.

Background: The sudden emergence of novel influenza viruses is a global public health concern. Conventional influenza vaccines targeting the highly variable surface glycoproteins hemagglutinin and neuraminidase must antigenically match the emerging strain to be effective. In contrast, "universal" vaccines targeting conserved viral components could be used regardless of viral strain or subtype.

Genetic control of immune responses to influenza A matrix 2 protein (M2).

Vaccines should protect genetically diverse populations. Therefore we tested the candidate "universal" influenza A matrix protein 2 (M2) vaccine in multiple mouse strains. Mice were primed with M2 DNA and boosted with M2 recombinant adenovirus (rAd).

Vaccination focusing immunity on conserved antigens protects mice and ferrets against virulent H1N1 and H5N1 influenza A viruses.

Immunization against conserved virus components induces broad, heterosubtypic protection against diverse influenza A viruses, providing a strategy for controlling unexpected outbreaks or pandemics until strain-matched vaccines become available. This study characterized immunization to nucleoprotein (NP) and matrix 2 (M2) by DNA priming followed by parenteral or mucosal boosting in mice and ferrets. DNA vaccination followed by boosting with antigen-matched recombinant adenovirus (rAd) or cold-adapted (ca) influenza virus provided robust protection against virulent H1N1 and H5N1 challenges.