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•Emergence of MERS-CoV demonstrates the need for novel vaccine strategies against coronaviruses.•Production of novel nanoparticle vaccine containing full spike protein of MERS-CoV and SARS-CoV.•Higher titer neutralizing antibody produced in vaccinated mice.•Vaccination in combination with a new adjuvant, Matrix M1, boosts neutralizing antibody titer. Development of vaccination strategies for emerging pathogens are particularly challenging because of the sudden nature of their emergence and the long process needed for traditional vaccine development. Therefore, there is a need for development of a rapid method of vaccine development that can respond to emerging pathogens in a short time frame. The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in late 2012 demonstrate the importance of coronaviruses as emerging pathogens. The spike glycoproteins of coronaviruses reside on the surface of the virion and are responsible for virus entry. The spike glycoprotein is the major immunodominant antigen of coronaviruses and has proven to be an excellent target for vaccine designs that seek to block coronavirus entry and promote antibody targeting of infected cells. Vaccination strategies for coronaviruses have involved live attenuated virus, recombinant viruses, non-replicative virus-like particles expressing coronavirus proteins or DNA plasmids expressing coronavirus genes. None of these strategies has progressed to an approved human coronavirus vaccine in the ten years since SARS-CoV emerged. Here we describe a novel method for generating MERS-CoV and SARS-CoV full-length spike nanoparticles, which in combination with adjuvants are able to produce high titer antibodies in mice.

The Middle East respiratory syndrome coronavirus (MERS-CoV) was first discovered in late 2012 and has gone on to cause over 1800 infections and 650 deaths. There are currently no approved therapeutics or vaccinations for MERS-CoV. The MERS-CoV spike (S) protein is responsible for receptor binding and virion entry to cells, is immunodominant and induces neutralizing antibodies in vivo, all of which, make the S protein an ideal target for anti-MERS-CoV vaccines. In this study, we demonstrate protection induced by vaccination with a recombinant MERS-CoV S nanoparticle vaccine and Matrix-M1 adjuvant combination in mice. The MERS-CoV S nanoparticle vaccine produced high titer anti-S neutralizing antibody and protected mice from MERS-CoV infection in vivo.

•Recombinant Ebola virus glycoprotein nanoparticle vaccine induces B and T cell responses in mice.•Matrix-M adjuvant provides significant immune response enhancement.•Ebola glycoprotein nanoparticle vaccine protects mice against a lethal Ebola virus challenge. Ebola virus (EBOV) causes severe hemorrhagic fever for which there is no approved treatment or preventive vaccine. Immunological correlates of protective immunity against EBOV disease are not well understood. However, non-human primate studies have associated protection of experimental vaccines with binding and neutralizing antibodies to the EBOV glycoprotein (GP) as well as EBOV GP-specific CD4+ and CD8+ T cells. In this report a full length, unmodified Zaire EBOV GP gene from the 2014 EBOV Makona strain (EBOV/Mak) was cloned into a baculovirus vector. Recombinant EBOV/Mak GP was produced in Sf9 insect cells as glycosylated trimers and, when purified, formed spherical 30–40nm particles. In mice, EBOV/Mak GP co-administered with the saponin adjuvant Matrix-M was significantly more immunogenic, as measured by virus neutralization titers and anti-EBOV/Mak GP IgG as compared to immunization with AlPO4 adjuvanted or non-adjuvanted EBOV/Mak GP. Similarly, antigen specific T cells secreting IFN-γ were induced most prominently by EBOV/Mak GP with Matrix-M. Matrix-M also enhanced the frequency of antigen-specific germinal center B cells and follicular helper T (TFH) cells in the spleen in a dose-dependent manner. Immunization with EBOV/Mak GP with Matrix-M was 100% protective in a lethal viral challenge murine model; whereas no protection was observed with the AlPO4 adjuvant and only 10% (1/10) mice were protected in the EBOV/Mak GP antigen alone group. Matrix-M adjuvanted vaccine induced a rapid onset of specific IgG and neutralizing antibodies, increased frequency of multifunctional CD4+ and CD8+ T cells, specific TFH cells, germinal center B cells, and persistence of EBOV GP-specific plasma B cells in the bone marrow. Taken together, the addition of Matrix-M adjuvant to the EBOV/Mak GP nanoparticles enhanced both B and T-cell immune stimulation which may be critical for an Ebola subunit vaccine with broad and long lasting protective immunity.

A Skin Prep System (SPS) has been developed to provide a well-tolerated and controlled method of stratum corneum disruption using mild abrasion as part of transcutaneous immunization (TCI). In this study, four groups ( n = 10) of volunteers were pretreated with the SPS using three different lengths of mild abrasive strips (13 mm, 25 mm and 38 mm), or a handheld applicator. They then received a vaccine patch containing 50 μg of the heat-labile enterotoxin from Escherichia coli (LT) at day 0 and day 21. Subsequent anti-LT IgG antibody responses were dependent on abrasive strip length, with highest immune responses seen after use of the longest strip. The development of a simple, single-use, disposable device that is well-tolerated and allows disruption to be modulated represents an important step forward in physical penetration enhancement for the skin.

•Recombinant A/Anhui/1/2013 (H7N9) HA, NA and avian M1 form virus like particles.•A(H7N9) VLP form enveloped particles containing HA and NA glycoproteins.•A(H7N9) VLP vaccine induced hemagglutinin inhibition (HAI) titers ≥1:64.•A(H7N9) VLP vaccine 100% protective against wild type A/Anhui/1/2013 (H7N9) influenza challenge.•A(H7N9) VLP vaccine in vivo data support clinical development in man. The recent emergence of severe human illness caused by avian-origin influenza A(H7N9) viruses in China has precipitated a global effort to rapidly develop and test vaccine candidates. To date, non-A(H7N9) H7 subtype influenza vaccine candidates have been poorly immunogenic and difficulties in production of A(H7N9) virus seed strains have been encountered. A candidate recombinant A(H7N9) vaccine consisting of full length, unmodified hemagglutinin (HA) and neuraminidase (NA) from the A/Anhui/1/2013 and the matrix 1 (M1) protein from the A/Indonesia/05/2005 (H5N1) were cloned into a baculovirus vector. Baculovirus infected Spodoptera frugiperda (Sf9) insect cells secreted virus like particles (VLP) composed of HA, NA, and M1 that resemble mature influenza virions. Genetic construction of vaccine from acquisition of an H7N9 genomic sequence to production of A(H7N9) VLP occurred in 26 days. The immunogenicity and efficacy of A/Anhui/1/2013 (H7N9) VLP vaccine administered on days 0 and 14 were evaluated in a lethal wild-type challenge Balb/c mouse model. Control groups included a non-homologous H7 vaccine (A/chicken/Jalisco/CPA1/2012 (H7N3)-VLP), and A/Indonesia/05/2005 (H5N1)-VLP, or placebo. All vaccines were administered with or without ISCOMATRIX. A(H7N9) VLP elicited hemagglutination-inhibition (HAI) antibody titers of ≥1:64 against the homologous virus, cross-reactive HAI against the heterologous A(H7N3), and 3- to 4-fold higher HAI responses in corresponding ISCOMATRIX subgroups. Similarly, all doses of H7N9 VLP elicited anti-neuraminidase (NA) antibody, with 3- to 4-fold higher responses measured in the corresponding ISCOMATRIX subgroups. The non-homologous H7 vaccine induced both H7N3 and H7N9 HAI but no N9 anti-NA antibodies. A lethal murine wild-type A/Anhui/1/2013 (H7N9) challenge demonstrated 100% survival of all animals receiving A(H7N9) and A(H7N3) vaccine, versus 0% survival in A(H5N1) vaccine and placebo groups. Together, the data demonstrate that recombinant H7N9 vaccine can be rapidly developed that was immunogenic and efficacious supporting testing in man as a pandemic influenza H7N9 vaccine candidate.

•RSV F nanoparticle vaccine induced palivizumab competing antibodies (PCA).•PCA is in excess of serum protective levels than IM injected palivizumab.•Live virus infection induces little or no PCA.•Passively administered RSV F antibodies protects cotton rats against RSV virus.•RSV F vaccine does not induce disease enhancement in comparison to Lot 100 FI-RSV. Post-infectious immunity to respiratory syncytial virus (RSV) infection results in limited protection as evidenced by the high rate of infant hospitalization in the face of high titer, maternally derived RSV-specific antibodies. By contrast, RSV fusion (F) glycoprotein antigenic site II humanized monoclonal antibodies, palivizumab and motavizumab, have been shown to reduce RSV-related hospitalization in infants. Immunogenicity and efficacy studies were conducted in cotton rats comparing a recombinant RSV F nanoparticle vaccine with palivizumab and controlled with live RSV virus intranasal immunization and, formalin inactivated RSV vaccine. Active immunization with RSV F nanoparticle vaccine containing an alum adjuvant induced serum levels of palivizumab competing antibody (PCA) greater than passive administration of 15mg/kg palivizumab (human prophylactic dose) in cotton rats and neutralized RSV-A and RSV-B viruses. Immunization prevented detectable RSV replication in the lungs and, unlike passive administration of palivizumab, in the nasal passage of challenged cotton rats. Histology of lung tissues following RSV challenge showed no enhanced disease in the vaccinated groups in contrast to formalin inactivated ‘Lot 100’ vaccine. Passive intramuscular administration of RSV F vaccine-induced immune sera one day prior to challenge of cotton rats reduced viral titers by 2 or more log10 virus per gram of lung and nasal tissue and at doses less than palivizumab. A recombinant RSV F nanoparticle vaccine protected lower and upper respiratory tract against both RSV A and B strain infection and induced polyclonal palivizumab competing antibodies similar to but potentially more broadly protective against RSV than palivizumab.

► C. difficile ToxinA:toxin B fusion protein. ► Induction of toxin neutralizing antibody. ► Immunoprotection against an in vivo C. difficile spore challenge. Antibodies targeting the Clostridium difficile toxin A and toxin B confer protective immunity to C. difficile associated disease in animal models and provided protection against recurrent C. difficile disease in human subjects. These antibodies are directed against the receptor binding domains (RBD) located in the carboxy-terminal portion of both toxins and inhibit binding of the toxins to their receptors. We have constructed a recombinant fusion protein containing portions of the RBD from both toxin A and toxin B and expressed it in Escherichia coli. The fusion protein induced high levels of serum antibodies to both toxins A and B capable of neutralizing toxin activity both in vitro and in vivo. In a hamster C. difficile infection model, immunization with the fusion protein reduced disease severity and conferred significant protection against a lethal dose of C. difficile spores. Our studies demonstrate the potential of the fusion protein as a vaccine that could provide protection from C. difficile disease in humans.

Enterotoxigenic Escherichia coli (ETEC) is a major cause of travellers' diarrhoea. We investigated the rate of diarrhoea attacks, safety, and feasibility of a vaccine containing heat-labile enterotoxin (LT) from ETEC delivered to the skin by patch in travellers to Mexico and Guatemala. In this phase II study, healthy adults (aged 18–64 years) who planned to travel to Mexico or Guatemala and had access to a US regional vaccination centre were eligible. A centralised randomisation code was used for allocation, which was masked to participants and site staff. Primary endpoints were to investigate the field rate of ETEC diarrhoea, and to assess the safety of heat-labile toxins from E coli (LT) delivered via patch. Secondary endpoints included vaccine efficacy against travellers' diarrhoea and ETEC. Participants were vaccinated before travel, with two patches given 2–3 weeks apart. Patches contained either 37·5 μg of LT or placebo. Participants tracked stool output on diary cards in country and provided samples for pathogen identification if diarrhoea occurred. Diarrhoea was graded by the number of loose stools in 24 h: mild (three), moderate (four or five), and severe (at least six). Analysis was per protocol. The trial is registered with ClinicalTrials.gov, number NCT00516659. Recruitment closed after 201 participants were assigned patches. 178 individuals received two vaccinations and travelled and 170 were analysed. 24 (22%) of 111 placebo recipients had diarrhoea, of whom 11 (10%) had ETEC diarrhoea. The vaccine was safe and immunogenic. The 59 LT-patch recipients were protected against moderate-to-severe diarrhoea (protective efficacy [PE] 75%, p=0·0070) and severe diarrhoea (PE 84%, p=0·0332). LT-patch recipients who became ill had shorter episodes of diarrhoea (0·5 days vs 2·1 days, p=0·0006) with fewer loose stools (3·7 vs 10·5, p<0·0001) than placebo. Travellers' diarrhoea is a common ailment, with ETEC diarrhoea illness occurring in 10% of cases. The vaccine patch is safe and feasible, with benefits to the rate and severity of travellers' diarrhoea. IOMAI Corporation.

An enterotoxigenic Escherichia coli (ETEC) vaccine could reduce diarrhea among children in developing countries and travelers to these countries. The heat-labile toxin (LT) of ETEC is immunogenic but too toxic for oral or nasal vaccines. In a double-blind, placebo-controlled trial, 59 adults were randomized to receive 50 μg of LT or placebo in a patch applied to alternating arms on days 0, 21, and 42. On day 56, 27 vaccinees and 20 controls were challenged orally with 6 × 10 8 cfu of LT +/ST + ETEC. 100 and 97% of vaccinees had 4-fold increases in anti-LT IgG and IgA, and 100 and 90% developed IgG- and IgA-antibody-secreting cell responses. The study did not meet the primary endpoint: 82% of vaccinees and 75% of controls had moderate to severe ETEC illness. However, vaccinees with ETEC illness had lower numbers (6.8 versus 9.7, p = 0.04) and weights of loose stools (840 g versus 1147 g, p < 0.05), a decreased need for intravenous fluids (14% versus 40%, p = 0.03) and a delayed onset of diarrhea (30 h versus 22 h, p = 0.01). Transcutaneous LT vaccination induced anti-toxin immune responses that did not prevent but mitigated illness following a high-dose challenge with a virulent LT +/ST + ETEC strain.

The skin is an attractive target for vaccine delivery. Adjuvants and antigens delivered into the skin can result in potent immune responses and an unmatched safety profile. The heat- labile enterotoxin (LT) from Echerichia coli, which acts both as antigen and adjuvant, has been shown to be delivered to human skin efficiently when used in a patch, resulting in strong immune responses. Iomai scientists have capitalized on these observations to develop late-stage products based on LT. This has encouraged commercial-level product development of a delivery system that is efficient, user-friendly and designed to address important medical needs. Over the past 2 years, extensive clinical testing and optimization has allowed the patch to evolve to a late-stage product. As a strategy for approval of a revolutionary vaccine-delivery system, the singular focus on optimization of LT delivery has enabled technical progress to extend patch-vaccine product development beyond LT. The field efficacy of the LT-based travelers' diarrhea vaccine has validated this approach. The discussion of transcutaneous immunization is unique, in that any consideration of the adjuvant must also include delivery, and the significant advances in a commercial patch application system are described. In this review, we integrate these concepts, update the clinical data and look to the future.