scholarly journals A thermostable oral SARS-CoV-2 vaccine induces mucosal and protective immunity

2021 ◽  
Author(s):  
Bertrand Bellier ◽  
Alicia Saura ◽  
Lucas A. Luján ◽  
Cecilia R. Molina ◽  
Hugo D. Lujan ◽  
...  
Keyword(s):  
Protective Immunity ◽  
Virus Transmission ◽  
Vaccination Strategy ◽  
Protein S ◽  
Surface Proteins ◽  
Enveloped Virus ◽  
Variable Surface ◽  
Mucosal Response ◽  
Logistic Chain ◽  
Simple Logistic

AbstractAn ideal protective vaccine against SARS-CoV-2 should not only be effective in preventing disease, but also in preventing virus transmission. It should also be well accepted by the population and have a simple logistic chain. To fulfill these criteria, we developed a thermostable, orally administered vaccine that can induce a robust mucosal neutralizing immune response. We used our platform based on retrovirus-derived enveloped virus-like particles (e-VLPs) harnessed with variable surface proteins (VSPs) from the intestinal parasite Giardia lamblia, affording them resistance to degradation and the triggering of robust mucosal cellular and antibody immune responses after oral administration. We made e-VLPs expressing various forms of the SARS-CoV-2 Spike protein (S), with or without membrane protein (M) expression. We found that prime-boost administration of VSP-decorated e-VLPs expressing a pre-fusion stabilized form of S and M triggers robust mucosal responses against SARS-CoV-2 in mice and hamsters, which translate into complete protection from a viral challenge. Moreover, they dramatically boosted the IgA mucosal response of intramuscularly injected vaccines. We conclude that our thermostable orally administered e-VLP vaccine could be a valuable addition to the current arsenal against SARS-CoV-2, in a stand-alone prime-boost vaccination strategy or as a boost for existing vaccines.

scholarly journals Conformational Plasticity of Hepatitis B Core Protein Spikes Promotes Peptide Binding Independent of the Secretion Phenotype

2021 ◽  
Vol 9 (5) ◽  
pp. 956
Author(s):  
Cihan Makbul ◽  
Vladimir Khayenko ◽  
Hans Michael Maric ◽  
Bettina Böttcher
Keyword(s):  
Hepatitis B ◽  
Core Protein ◽  
Peptide Binding ◽  
Surface Proteins ◽  
Binding Motif ◽  
Virus Particles ◽  
Enveloped Virus ◽  
Conformational Plasticity ◽  
Viral Maturation ◽  
Hepatitis B Core Protein

Hepatitis B virus is a major human pathogen, which forms enveloped virus particles. During viral maturation, membrane-bound hepatitis B surface proteins package hepatitis B core protein capsids. This process is intercepted by certain peptides with an “LLGRMKG” motif that binds to the capsids at the tips of dimeric spikes. With microcalorimetry, electron cryo microscopy and peptide microarray-based screens, we have characterized the structural and thermodynamic properties of peptide binding to hepatitis B core protein capsids with different secretion phenotypes. The peptide “GSLLGRMKGA” binds weakly to hepatitis B core protein capsids and mutant capsids with a premature (F97L) or low-secretion phenotype (L60V and P5T). With electron cryo microscopy, we provide novel structures for L60V and P5T and demonstrate that binding occurs at the tips of the spikes at the dimer interface, splaying the helices apart independent of the secretion phenotype. Peptide array screening identifies “SLLGRM” as the core binding motif. This shortened motif binds only to one of the two spikes in the asymmetric unit of the capsid and induces a much smaller conformational change. Altogether, these comprehensive studies suggest that the tips of the spikes act as an autonomous binding platform that is unaffected by mutations that affect secretion phenotypes.

scholarly journals Hepatitis C virus entry into the hepatocyte

2011 ◽  
Vol 6 (6) ◽  
pp. 933-945 ◽  
Author(s):  
Sandrine Belouzard ◽  
Laurence Cocquerel ◽  
Jean Dubuisson
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Current Knowledge ◽  
Virus Entry ◽  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Surface Proteins ◽  
Enveloped Virus ◽  
Early Endosomes

AbstractHepatitis C virus (HCV) is a small enveloped virus with a positive stranded RNA genome belonging to the Flaviviridae family. The virion has the unique ability of forming a complex with lipoproteins, which is known as the lipoviroparticle. Lipoprotein components as well as the envelope proteins, E1 and E2, play a key role in virus entry into the hepatocyte. HCV entry is a complex multistep process involving sequential interactions with several cell surface proteins. The virus relies on glycosaminoglycans and possibly the low-density lipoprotein receptors to attach to cells. Furthermore, four specific entry factors are involved in the following steps which lead to virus internalization and fusion in early endosomes. These molecules are the scavenger receptor SRB1, tetraspanin CD81 and two tight junction proteins, Claudin-1 and Occludin. Although they are essential to HCV entry, the precise role of these molecules is not completely understood. Finally, hepatocytes are highly polarized cells and which likely affects the entry process. Our current knowledge on HCV entry is summarized in this review.

scholarly journals Mycobacterium bovis BCG Surface Antigens Expressed under the Granuloma-Like Conditions as Potential Inducers of the Protective Immunity

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Yingyu Chen ◽  
Lia Danelishvili ◽  
Sasha J. Rose ◽  
Luiz E. Bermudez
Keyword(s):  
Mycobacterium Bovis ◽  
Recombinant Proteins ◽  
Protective Immunity ◽  
Bacterial Load ◽  
Surface Antigens ◽  
Surface Proteins ◽  
Host Cells ◽  
Biologically Relevant ◽  
Mucosal Cells ◽  
Potential Reservoir

Bovine tuberculosis (bTB) is a highly transmissible infection and remains of great concern as a zoonosis. The worldwide incidence of bTB is in rise, creating potential reservoir and increased infection risk for humans and animals. In attempts to identify novel surface antigens of Mycobacterium bovis as a proof-of-concept for potential inducers of protective immunity, we investigated surface proteome of M. bovis BCG strain that was cultured under the granuloma-like condition. We also demonstrated that the pathogen exposed to the biologically relevant environment has greater binding and invasion abilities to host cells than those of bacteria incubated under regular laboratory conditions. A total of 957 surface-exposed proteins were identified for BCG cultured under laboratory condition, whereas 1,097 proteins were expressed under the granuloma-like condition. The overexpression of Mb1524, Mb01_03198, Mb1595_p3681 (PhoU1 same as phoY1_1), and Mb1595_p0530 (HbhA) surface proteins in Mycobacterium smegmatis leads to increased binding and invasion to mucosal cells. We also examined the immunogenicity of purified recombinant proteins and tested M. smegmatis overexpressing these surface antigens for the induction of protective immunity in mice. Significantly high levels of specific IgA and IgG antibodies were observed in recombinant protein immunized groups by both inhalation and intraperitoneal (IP) routes, but only IP delivery induced high total IgA and IgG levels. We did not detect major differences in antibody levels in the M. smegmatis group that overexpressed surface antigens. In addition, the bacterial load was significantly reduced in the lungs of mice immunized with the combination of inhaled recombinant proteins. Our findings suggest that the activation of the mucosal immunity can lead to increased ability to confer protection upon M. bovis BCG infection.

scholarly journals Contributions of the Avian Influenza Virus HA, NA, and M2 Surface Proteins to the Induction of Neutralizing Antibodies and Protective Immunity

2009 ◽  
Vol 84 (5) ◽  
pp. 2408-2420 ◽  
Author(s):  
Baibaswata Nayak ◽  
Sachin Kumar ◽  
Joshua M. DiNapoli ◽  
Anandan Paldurai ◽  
Daniel R. Perez ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Avian Influenza ◽  
Avian Influenza Virus ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Reverse Genetics ◽  
Severe Disease ◽  
Serum Antibody ◽  
Surface Proteins ◽  
Serum Antibodies

ABSTRACT Highly pathogenic avian influenza virus (HPAIV) subtype H5N1 causes severe disease and mortality in poultry. Increased transmission of H5N1 HPAIV from birds to humans is a serious threat to public health. We evaluated the individual contributions of each of the three HPAIV surface proteins, namely, the hemagglutinin (HA), the neuraminidase (NA), and the M2 proteins, to the induction of HPAIV-neutralizing serum antibodies and protective immunity in chickens. Using reverse genetics, three recombinant Newcastle disease viruses (rNDVs) were engineered, each expressing the HA, NA, or M2 protein of H5N1 HPAIV. Chickens were immunized with NDVs expressing a single antigen (HA, NA, and M2), two antigens (HA+NA, HA+M2, and NA+M2), or three antigens (HA+NA+M2). Immunization with HA or NA induced high titers of HPAIV-neutralizing serum antibodies, with the response to HA being greater, thus identifying HA and NA as independent neutralization antigens. M2 did not induce a detectable neutralizing serum antibody response, and inclusion of M2 with HA or NA reduced the magnitude of the response. Immunization with HA alone or in combination with NA induced complete protection against HPAIV challenge. Immunization with NA alone or in combination with M2 did not prevent death following challenge, but extended the time period before death. Immunization with M2 alone had no effect on morbidity or mortality. Thus, there was no indication that M2 is immunogenic or protective. Furthermore, inclusion of NA in addition to HA in a vaccine preparation for chickens may not enhance the high level of protection provided by HA.

Adhesion properties of potentially probioticLactobacillus kefirito gastrointestinal mucus

2013 ◽  
Vol 81 (1) ◽  
pp. 16-23 ◽  
Author(s):  
Paula Carasi ◽  
Nicolás M. Ambrosis ◽  
Graciela L. De Antoni ◽  
Philippe Bressollier ◽  
María C. Urdaci ◽  
...  
Keyword(s):  
Bacterial Adhesion ◽  
Significant Proportion ◽  
Surface Protein ◽  
Protein S ◽  
Surface Proteins ◽  
Binding Properties ◽  
Added Sugar ◽  
Adhesion Properties ◽  
Probiotic Strains ◽  
Lactobacillus Kefiri

We investigated the mucus-binding properties of aggregating and non-aggregating potentially probiotic strains of kefir-isolatedLactobacillus kefiri, using different substrates. All the strains were able to adhere to commercial gastric mucin (MUCIN) and extracted mucus from small intestine (SIM) and colon (CM). The extraction of surface proteins from bacteria using LiCl or NaOH significantly reduced the adhesion of three selected strains (CIDCA 8348, CIDCA 83115 and JCM 5818); although a significant proportion (up to 50%) of S-layer proteins were not completely eliminated after treatments. The surface (S-layer) protein extracts from all the strains ofLb. kefiriwere capable of binding to MUCIN, SIM or CM, and no differences were observed among them. The addition of their own surface protein extract increased adhesion of CIDCA 8348 and 83115 to MUCIN and SIM, meanwhile no changes in adhesion were observed for JCM 5818. None of the seven sugars tested had the ability to inhibit the adhesion of whole bacteria to the three mucus extracts. Noteworthy, the degree of bacterial adhesion reached in the presence of their own surface protein (S-layer) extract decreased to basal levels in the presence of some sugars, suggesting an interaction between the added sugar and the surface proteins. In conclusion, the ability of these food-isolated bacteria to adhere to gastrointestinal mucus becomes an essential issue regarding the biotechnological potentiality ofLb. kefirifor the food industry.

scholarly journals Composition of the Surface Proteome of Anaplasma marginale and Its Role in Protective Immunity Induced by Outer Membrane Immunization

2008 ◽  
Vol 76 (5) ◽  
pp. 2219-2226 ◽  
Author(s):  
Susan M. Noh ◽  
Kelly A. Brayton ◽  
Wendy C. Brown ◽  
Junzo Norimine ◽  
Gerhard R. Munske ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Protective Immunity ◽  
Vaccine Development ◽  
Bacterial Pathogen ◽  
Protein Composition ◽  
Anaplasma Marginale ◽  
Surface Proteins ◽  
Mammalian Host ◽  
Surface Complexes ◽  
Surface Proteome

ABSTRACT Surface proteins of tick-borne, intracellular bacterial pathogens mediate functions essential for invasion and colonization. Consequently, the surface proteome of these organisms is specifically relevant from two biological perspectives, induction of protective immunity in the mammalian host and understanding the transition from the mammalian host to the tick vector. In this study, the surface proteome of Anaplasma marginale, a tick-transmitted bacterial pathogen, was targeted by using surface-specific cross-linking to form intermolecular bonds between adjacent proteins. Liquid chromatography and tandem mass spectroscopy were then employed to characterize the specific protein composition of the resulting complexes. The surface complexes of A. marginale isolated from erythrocytes of the mammalian host were composed of multiple membrane proteins, most of which belong to a protein family, pfam01617, which is conserved among bacteria in the genus Anaplasma and the closely related genus Ehrlichia. In contrast, the surface proteome of A. marginale isolated from tick cells was much less complex and contained a novel protein, AM778, not identified within the surface proteome of organisms from the mammalian host. Immunization using the cross-linked surface complex induced protection against high-level bacteremia and anemia upon A. marginale challenge of cattle and effectively recapitulated the protection induced by immunization with whole outer membranes. These results indicate that a surface protein subset of the outer membrane is capable of inducing protective immunity and serves to direct vaccine development. Furthermore, the data support that remodeling of the surface proteome accompanies the transition between mammalian and arthropod hosts and identify novel targets for blocking transmission.

scholarly journals Evidence of possible evasion of protective immunity by NAD-independent isolates of Haemophilus paragallinarum in poultry

2004 ◽  
Vol 71 (1) ◽  
Author(s):  
R.R. Bragg
Keyword(s):  
Immune System ◽  
Immune Evasion ◽  
Protective Immunity ◽  
Reference Strain ◽  
Vaccination Strategy ◽  
The Other ◽  
Control Methods ◽  
Alternative Control ◽  
Significant Difference ◽  
Alternative Control Methods

An indication of the ability of NAD-independent variants of Haemophilus paragallinarum to evade the immune system has been obtained from data obtained from several experiments. Firstly, it was noted that there was a difference in the serovar distribution between the NAD-dependent isolates in the 1990s and the NAD-independent isolates, as there was a significant decrease in the incidence of serogroup A NAD-dependent isolates. This can possibly be attributed to the extensive use of vaccines. On the other hand, most of the earlier NAD-independent isolates were serovar A. This is a possible indication of evasion of the protective immunity by the NAD-independent isolates. Further evidence of possible evasion of the protective immunity was obtained from results obtained when different isolates, both NAD dependent and NAD independent, were tested with a panel of monoclonal antibodies (Mabs). The V1 Mab reaction pattern was only seen in the reference strain 0083 among all of the NAD-dependent isolates tested in South Africa. This Mab was, however, found to react with some of the NAD-independent isolates. Furthermore, the isolation of NAD-dependent isolates in Australia which react with the V1 Mab also suggest possible evasion of the protective immunity by the NAD-independent isolates as no vaccines containing strain 0083 are used in Australia. In order to investigate the hypothesis of immune-evasion by NAD-independent H. paragallinarum, vaccinated and unvaccinated chickens were challenged with a NAD-independent serogroup C isolate. As a control, chickens were also challenged with NAD-dependent H. paragallinarum of the same serogroup. The results obtained indicate that there is no significant difference in the disease profiles obtained in vaccinated and unvaccinated chickens challenged with the NAD-independent isolate, thus providing further evidence of evasion of the productivity immunity by the NAD-independent isolates. The ability of the NAD-independent isolates to evade the immune system suggests that a different vaccination strategy, or alternative control methods may be needed for the control of IC caused by these isolates.

scholarly journals Characterization of a Multigene Family Undergoing High-Frequency DNA Rearrangements and Coding for Abundant Variable Surface Proteins in Mycoplasma agalactiae

2000 ◽  
Vol 68 (8) ◽  
pp. 4539-4548 ◽  
Author(s):  
M. D. Glew ◽  
L. Papazisi ◽  
F. Poumarat ◽  
D. Bergonier ◽  
R. Rosengarten ◽  
...  
Keyword(s):  
Phase Variation ◽  
Gene Families ◽  
Surface Proteins ◽  
Dna Rearrangements ◽  
Reading Frame ◽  
Mycoplasma Agalactiae ◽  
Amino Terminal ◽  
Clonal Variant ◽  
Variable Surface

ABSTRACT A family of abundant surface proteins (Vpmas [variable proteins ofMycoplasma agalactiae]) undergoing phase variation inM. agalactiae has been characterized using monoclonal antibodies and specific polyclonal sera. Two expressed members of 39 kDa (Vpma39) and 34 kDa (Vpma34), which varied in expression between clones of a lineage, shared a common amino-terminal sequence but were immunologically distinct. An amino-terminal oligonucleotide probe identified multiple vpma genes which were clustered within a 14-kb ClaI genomic fragment. Rearrangements were found to have occurred within the vpma locus between clones which correlated with changes in their Vpma phenotype. Two neighboringvpma genes were cloned and sequenced from one M. agalactiae clonal variant expressing Vpma39. The two genes,vpmaX and vpmaY, were orientated divergently and shared highly homologous 5′ untranslated regions, 25-amino-acid (aa) lipoprotein leader sequences, and amino-terminal sequences. ThevpmaY gene coded for 346 aa and 84% of the open reading frame, comprised of 1.5 units of a large repeat of 186 aa. Although the sequence for an entire second vpmaY repeat was present, it was prematurely terminated by insertion of two nucleotides. ThevpmaX gene encoded 221 aa and possessed 102 aa of the 186-aa repeat of vpmaY. Many of the features in common between the vpma genes were also found to be shared by thevsp genes of M. bovis, which also undergo DNA rearrangements concomitant with phenotypic changes. Since M. bovis is the closest phylogenetic relative to M. agalactiae, the vpma and vsp gene families most probably represent homologous systems.

scholarly journals Adapting French COVID-19 vaccination campaign duration to variant dissemination

2021 ◽  
Author(s):  
Simon Pageaud ◽  
Nicolas Ponthus ◽  
Romain Gauchon ◽  
Catherine Pothier ◽  
Christophe Rigotti ◽  
...  
Keyword(s):  
Disease Transmission ◽  
Vaccination Campaign ◽  
Virus Transmission ◽  
International Health ◽  
Vaccination Strategy ◽  
Health Crisis ◽  
Population Immunity ◽  
Best Response ◽  
Rapid Dissemination ◽  
Vaccination Campaigns

Background The outbreak of SARS-CoV-2 virus has caused a major international health crisis with serious consequences in terms of public health and economy. In France, two lockdown periods were decided in 2020 to avoid the saturation of intensive care units (ICU) and an increase in mortality. The rapid dissemination of variant SARS-CoV-2 VOC 202012/01 has strongly influenced the course of the epidemic. Vaccines have been rapidly developed. Their efficacy against the severe forms of the disease has been established, and their efficacy against disease transmission is under evaluation. The aim of this paper is to compare the efficacy of several vaccination strategies in the presence of variants in controlling the COVID-19 epidemic through population immunity. Methods An agent-based model was designed to simulate with different scenarios the evolution of COVID-19 pandemic in France over 2021 and 2022. The simulations were carried out ignoring the occurrence of variants then taking into account their diffusion over time. The expected effects of three Non-Pharmaceutical Interventions (Relaxed-NPI, Intensive-NPI, and Extended-NPI) to limit the epidemic extension were compared. The expected efficacy of vaccines were the values recently estimated in preventing severe forms of the disease (75% and 94%) for the current used vaccines in France (Pfizer-BioNTech and Moderna since January 11, 2021, and AstraZeneca since February 2, 2021). All vaccination campaigns reproduced an advanced age-based priority advised by the Haute Autoritć de Santć. Putative reductions of virus transmission were fixed at 0, 50, 75 and 90%. The effects of four vaccination campaign durations (6-month, 12-month, 18-month and 24-month) were compared. Results In the absence of vaccination, the presence of variants led to reject the Relaxed-NPI because of a high expected number of deaths (170 to 210 thousands) and the significant overload of ICUs from which 35 thousand patients would be deprived. In comparison with the situation without vaccination, the number of deaths was divided by 7 without ICU saturation with a 6-month vaccination campaign. A 12-month campaign would divide the number of deaths by 3 with Intensive-NPI and by 6 with Extended-NPI (the latter being necessary to avoid ICU saturation). With 18-month and 24-month vaccination campaigns without Extended-NPI, the number of deaths and ICU admissions would explode. Conclusion Among the four compared strategies the 6-month vaccination campaign seems to be the best response to changes in the dynamics of the epidemic due to the variants. The race against the COVID-19 epidemic is a race of vaccination strategy. Any further vaccination delay would increase the need of strengthened measures such as Extended-NPI to limit the number of deaths and avoid ICU saturation.

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