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Human immunodeficiency virus (HIV)-1 is mainly transmitted mucosally during sexual intercourse. We therefore evaluated the protective efficacy of a vaccine active at mucosal sites. Macaca mulatta monkeys were immunized via both the intramuscular and intranasal routes with an HIV-1 vaccine made of gp41-subunit antigens grafted on virosomes, a safe d...
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... the virosomes used in the present study are not designed for triggering a CTL response (Amacker et al., 2005; Wilschut 2009), we limited our investigation to the humoral response. In the serum at week 24, the rgp41-and P1-specific IgG and IgA responses were observed in almost all animals in group 2 (i.m. only), whereas in group 3 (i.m.+i.n.), the response was not always detectable (Table 1). At the mucosal level at week 24, gp41-and P1-specific IgAs were detected in cervico- vaginal secretions (CVSs) and rectal secretions (RSs) of most immunized and protected animals. ...
Context 2
... mucosal IgGs, only rgp41-specific IgGs, but not P1-specific IgGs, could be detected (not shown). A sizeable immune response required four immunizations as indicated by analyses of the samples at weeks 8 and 16 (Tables S1 and S2 available online). Overall, the mucosal immune response detected here may have been underestimated because detection of mucosal antibodies is always limited by the minute quantity of fluid that can be collected at each sampling time and by the dilution factor. ...
Citations
... Liposomes coated with the entire gp41 subunit or MPER peptides increased antibody titers. This may cause weak to moderate neutralization and cross-reactivity [85,125,126]. Virosomes delivered gp41 as part of a mucosal vaccination technique that caused NAbs to develop in the vagina of vaccinated nonhuman primates (NHPs) and protected most animals when challenged [127]. Most Phase I trial participants had mucosal antibodies [128]. ...
Vaccination has made an enormous contribution to global health. Treatment resistance for infectious diseases is growing quickly, and chemotherapeutic toxicity in cancer means that vaccines must be made right away to save humanity. But subunit vaccinations alone don't give enough strong and long-lasting protection against infections that can kill. Nanoparticle (NP)-based delivery vehicles, such as dendrimers, liposomes, micelles, virosomes, nanogels, and microemulsions, offer interesting ways to get around the problems with traditional vaccine adjuvants. The nanovaccines (50-250 nm in size) are most efficient in terms of tissue targeting, staying in the bloodstream for a long time. Nanovaccines can improve antigen presentation, targeted delivery, stimulation of the body's innate immune system, and a strong T-cell response without putting people at risk. This can help fight infectious diseases and cancers. Also, nanovaccines can be very helpful for making cancer treatments that use immunotherapy. So, this review highlights the various types of NPs used in the techniques that have worked in the new paradigm in viral vaccinology for infectious diseases. It gives a full rundown of the current NP-based vaccines, their potential as adjuvants, and the ways they can be delivered to cells. In the future, the best nanovaccines will try to be more logically designed, have more antigens in them, be fully functionalized, and be given to the right people.
... Influenza virosomes retain the hemagglutinin protein (HA) of the virus, which promotes the uptake of the virosomes by APCs and the delivery of antigens to the cytosol by fusion between the endosomal and the virosomal membrane [17,18]. Virosomes can be produced with peptide or protein antigens covalently linked to lipids of the membrane to induce strong immune responses against those antigens [19][20][21] and have been marketed as influenza and Hepatitis A vaccines [16,22]. Virosomes have been shown to induce strong CTL responses [23,24], and virosomes presenting the HPV16 E7 protein induced the survival of vaccinated mice challenged with TC-1 cells [18]. ...
... Promising clinical results have already been obtained with therapeutic vaccination using SLPs targeting HPV16 E6 and E7 oncoproteins combined with chemotherapy in cervical cancer [4] [2] and combined with anti-PD-1 in head & neck cancer [35,36], using Montanide as an adjuvant (2) Modification of the peptides with Amplivant fosters induction of Th1 T helper responses and sustained and robust CTL responses [37]. (3) Virosomes are nanoparticles that are particularly effective at presenting a variety of antigens, from HIV proteins and peptides to allergy-related antigens [19,21]. Virosomes without adjuvant containing soluble HPV 16 E7 protein in the lumen of the virosomes can induce CD8 + T cells and prevent tumor outgrowth in a prophylactic vaccination model [38]. ...
Therapeutic cancer vaccines trigger CD4 + and CD8 + T cell responses capable of established tumor eradication. Current platforms include DNA, mRNA and synthetic long peptide (SLP) vaccines, all aiming at robust T cell responses. SLPs linked to the Amplivant® adjuvant (Amplivant-SLP) have shown effective delivery to dendritic cells, resulting in improved immunogenicity in mice. We have now tested virosomes as a delivery vehicle for SLPs. Virosomes are nanoparticles made from influenza virus membranes and have been used as vaccines for a variety of antigens. Amplivant-SLP virosomes induced the expansion of more antigen-specific CD8 + T memory cells in ex vivo experiments with human PBMCs than Amplivant-SLP conjugates alone. The immune response could be further improved by including the adjuvants QS-21 and 3D-PHAD in the virosomal membrane. In these experiments, the SLPs were anchored in the membrane through the hydrophobic Amplivant adjuvant. In a therapeutic mouse model of HPV16 E6/E7⁺ cancer, mice were vaccinated with virosomes loaded with either Amplivant-conjugated SLPs or lipid-coupled SLPs. Vaccination with both types of virosomes significantly improved the control of tumor outgrowth, leading to elimination of the tumors in about half the animals for the best combinations of adjuvants and to their survival beyond 100 days.
... The intranasal vaccines, targeting nasal epithelial cells and dendritic cells, against mucosal HIV infection with P1 peptide was previously seen to be effective as a vaccine antigen that provided full protection. The P1 adjuvant was seen to be activating mucosal dendritic cells leading to Th2 cytokines and chemokine secretion that can induce mucosal humoral responses [279,280]. Another study conducted by Barnowski et al., on the effectiveness of flagellin protein, in HIV vaccine development as an adjuvant, showed that it induced innate immune response because of its affinity towards toll-like receptor 5 (TLR5). The study investigated a truncated membrane-bound form of the flagellin protein KFD adjuvant combined with an HIV-based VLP vaccine. ...
Immunization has the potential to become a viable weapon for the upcoming pandemic and save millions of lives, while also dramatically lowering the high mortality rate brought on by a number of infectious and chronic illnesses. Despite the success of some vaccinations for infectious illnesses, obstacles remain in avoiding and creating fully protective vaccines. Current COVID-19 pandemic highlights need for vaccination platform improvements. Nanomaterials have been created as a possible nanocarrier to elicit a robust immune response against important global morbidity and mortality drivers by encapsulating targeted antigen and functionalizing nanoparticles with particular molecules. In addition to their application in cancer immunotherapy, nanocarriers are currently being included into the development of vaccines against human immunodeficiency virus (HIV), malaria, TB, and influenza. In order to evaluate conventional and next-generation vaccination platforms, this study focuses on the COVID-19 and cancer vaccine as well as the passage and interaction of nanoparticles with immune cells in the lymph node. It also draws attention to the gaps in current and future HIV, TB, malaria, and influenza vaccinations, as well as nanovaccines. The importance of the dose-dependent vaccine in inducing and maintaining neutralizing antibodies after immunization has been discussed in more detail.
... 29 Although gp120-specific ADCC has most consistently been associated with protection, ADCC directed against the gp41 subunit correlated with protection or reduced viremia in multiple animal studies. 42,43 As such, few studies have taken a holistic approach to identify the lineages of mAbs that comprise plasma ADCC responses and how these Abs interact to promote potent cell killing. ...
Human natural history and vaccine studies support a protective role of antibody dependent cellular cytotoxicity (ADCC) activity against many infectious diseases. One setting where this has consistently been observed is in HIV-1 vertical transmission, where passively acquired ADCC activity in HIV-exposed infants has correlated with reduced acquisition risk and reduced pathogenesis in HIV+ infants. However, the characteristics of HIV-specific antibodies comprising a maternal plasma ADCC response are not well understood. Here, we reconstructed monoclonal antibodies (mAbs) from memory B cells from late pregnancy in mother MG540, who did not transmit HIV to her infant despite several high-risk factors. Twenty mAbs representing 14 clonal families were reconstructed, which mediated ADCC and recognized multiple HIV Envelope epitopes. In experiments using Fc-defective variants, only combinations of several mAbs accounted for the majority of plasma ADCC of MG540 and her infant. We present these mAbs as evidence of a polyclonal repertoire with potent HIV-directed ADCC activity.
... As the gp41 trimer changes conformationally during fusion, it can elicit unique humoral factors, the presentation of gp41 in a manner most relevant to disease progression is paramount in a vaccine (Bélec et al. 2001, Broliden et al. 2001, Coëffier et al. 2000, Devito et al. 2000). An antigen spanning the gp41 MPER and part of the C-terminal heptad repeat that was presented on a liposome to mimic insertion of the peptide in a membrane was found to elicit systemic and mucosal antibodies in both humans and macaques and was protective against a vaginal SHIV viral challenge in macaques (Bomsel et al. 2011, Leroux-Roels et al. 2013). To elicit a relevant immune response to this weak antigen, dgp41 was co-expressed with Gag to form a VLP presenting the gp41 antigen in a state that mimics their natural association with the cell membrane. ...
The Human Immunodeficiency Virus is responsible for an unprecedented global pandemic and is estimated to have claimed millions of lives globally. Over the years, much research has been conducted to develop an efficacious HIV vaccine to prevent infection and to develop antiretrovirals to suppress the virus in infected hosts. To date, RV144 is the only vaccine to demonstrate efficacy in clinical trials, although the impact was modest and below the threshold required for licensure. The development of effective antiretroviral therapies (ARTs) prevent the inevitable progression to AIDS-defining illness and by suppressing viral replication to undetectable levels and also prevents viral transmission. However, the widespread implementation of ARTs has not been sufficient to eradicate the virus, with the hardest hit populaces residing in sub-Saharan Africa. The inaccessibility and cost of ARTs during the early days of the pandemic hindered our ability to slow the rampant spread of the virus. The development of a vaccine poses an unprecedented scientific challenge and in the absence of protective immunization, other interventions and adherence to antiretroviral treatments are critical. Over the past twenty years, vaccines, monoclonal antibodies and other antiviral agents have been produced using plants as an alternative expression platform. Plant-based biopharmaceuticals are cheaper to produce than using mammalian cell culture platforms and easy to upscale for large scale biopharmaceutical production, making them appealing for developing countries. In this chapter, we present the history of the HIV/AIDS pandemic and provide examples of plant-made prophylactics developed to combat HIV and candidate vaccines based on HIV epitopes, full length proteins and virus-like particles. We review the generation of plant-made monoclonal antibodies to combat HIV and plant-made antiretrovirals to block the entry of the virus into infected host cells and its viral replication. Stable and transient expression of biologics are also discussed. This chapter ends with a discussion and recommendations of the steps required for plant-made pharmaceuticals to make an impact on the eradication of HIV/AIDS.
... Cervical IgA responses against gp41 [20] have been confirmed in cohorts of chronically exposed uninfected individuals [21]. Similar responses can be raised by gp41 vaccination and have shown protection of primates against mucosal challenge with SHIV [22]. Most Abs have no effect on viremia [23], but recent studies have suggested that Abs targeting specific epitopes may affect viremia. ...
Identifying epitope targets by studying the native antibody (Ab) response can identify potential novel vaccine constructs. Studies suggest that long-term non-progressor (LTNP) subjects have inherent immune mechanisms that help to control viremia and disease progression. To explore a role for antibodies (Abs) in LTNP progression, our lab has previously characterized a number of highly mutated Abs that target conformational epitopes of the human immunodeficiency virus (HIV) envelope protein from a single LTNP subject (10076). One Ab clone, 10076-Q3-2C6, had significant cross-clade Ab-dependent cell cytotoxicity. To assess if other LTNP subjects produced similar Abs, we expressed another highly mutated Ab from another subject; subject 10002, clone 10002-Q1-3F2 (variable heavy chain, 63.2% amino acid sequence identity to predicted germline). After expression with its native light chain, the recombinant Ab 3F2 bound to the trimeric envelope protein of HIV (trimer), as well as to the ectodomain of gp41. 3F2 binding to gp41 peptide libraries was consistent with non-linear epitope binding and showed possible overlap with the epitope of 2C6. Ab competition assays suggested that 3F2 may bind near the immunodominant epitope 1 loop region (ID1) of gp41. 2C6 blocked the binding of ID1-loop-binding Abs and 3F2 to the trimer, but 3F2 failed to block 2C6 binding. Together, these results suggest that 3F2 binds to a non-linear conformational epitope primarily localized between the epitope of 2C6 and the ID1. Since they are targeted by functional Abs, a more complete understanding of these ID1 and near-ID1 epitopes may be exploited in future immunization strategies.
... Establishment of antigen-specific SIgA antibodies at mucosal surfaces provides a frontline defense that can help prevent infection and transmission (10). With HIV, where 90% of transmissions occur through mucosal routes, induction of mucosal IgA responses, in combination with systemic IgG, has been found to be effective in promoting protection against mucosal simianhuman immunodeficiency virus (SHIV) challenge in primates (11,12). Similarly, SARS-CoV-2 clinical studies have shown that mucosal IgA exhibits potent neutralization and is a strong correlate of protection against the virus, which primarily infects cells in the upper and lower respiratory mucosa (13,14). ...
... By contrast, intranasal amph-protein immunization in nonhuman primates elicited enhanced systemic and nasal IgG and IgA responses compared to soluble protein administration, but distal mucosal responses in the vaginal tract and rectum were not sustained. Such "common mucosal immunity" has been reported in other small studies in macaques (1,11,(75)(76)(77) and humans. For example, intranasal immunization with the strong mucosal adjuvant cholera toxin B in humans elicited antibody responses in urine or vaginal secretions (78,79). ...
To combat the HIV epidemic and emerging threats such as SARS-CoV-2, immunization strategies are needed that elicit protection at mucosal portals of pathogen entry. Immunization directly through airway surfaces is effective in driving mucosal immunity, but poor vaccine uptake across the mucus and epithelial lining is a limitation. The major blood protein albumin is constitutively transcytosed bidirectionally across the airway epithelium through interactions with neonatal Fc receptors (FcRn). Exploiting this biology, here, we demonstrate a strategy of “albumin hitchhiking” to promote mucosal immunity using an intranasal vaccine consisting of protein immunogens modified with an amphiphilic albumin-binding polymer-lipid tail, forming amph-proteins. Amph-proteins persisted in the nasal mucosa of mice and nonhuman primates and exhibited increased uptake into the tissue in an FcRn-dependent manner, leading to enhanced germinal center responses in nasal-associated lymphoid tissue. Intranasal immunization with amph-conjugated HIV Env gp120 or SARS-CoV-2 receptor binding domain (RBD) proteins elicited 100- to 1000-fold higher antigen-specific IgG and IgA titers in the serum, upper and lower respiratory mucosa, and distal genitourinary mucosae of mice compared to unmodified protein. Amph-RBD immunization induced high titers of SARS-CoV-2–neutralizing antibodies in serum, nasal washes, and bronchoalveolar lavage. Furthermore, intranasal amph-protein immunization in rhesus macaques elicited 10-fold higher antigen-specific IgG and IgA responses in the serum and nasal mucosa compared to unmodified protein, supporting the translational potential of this approach. These results suggest that using amph-protein vaccines to deliver antigen across mucosal epithelia is a promising strategy to promote mucosal immunity against HIV, SARS-CoV-2, and other infectious diseases.
... Our results also demonstrate that the hybridoma-derived IgAs can transit through the harsh environment of the gastrointestinal tract and retain binding capability against bacterial antigens. This observation implies the potential usage of in vitro engineered IgA antibodies as therapeutics (40,(50)(51)(52). Compared with naturally secreted IgA antibodies, those hybridoma-derived IgAs lack the bound secretory component, which may ultimately compromise their stability to bacterial proteases in the gut lumen (53,54). ...
Despite being the most abundantly secreted immunoglobulin isotype, the pattern of reactivity of immunoglobulin A (IgA) antibodies toward each individual’s own gut commensal bacteria still remains elusive. By colonizing germ-free mice with defined commensal bacteria, we found that the binding specificity of bulk fecal and serum IgA toward resident gut bacteria resolves well at the species level and has modest strain-level specificity. IgA hybridomas generated from lamina propria B cells of gnotobiotic mice showed that most IgA clones recognized a single bacterial species, whereas a small portion displayed cross-reactivity. Orally administered hybridoma-produced IgAs still retained bacterial antigen binding capability, implying the potential for a new class of therapeutic antibodies. Species-specific IgAs had a range of strain specificities. Given the distinctive bacterial species and strain composition found in each individual’s gut, our findings suggest the IgA antibody repertoire is shaped uniquely to bind “self” gut bacteria.
... Consequently, the induced Ab isotype will be determinant for their functions, as well as the quantity and quality of the Fc receptors (FcRs) expressed on immune cells. Fc-mediated inhibitory functions, such as Ab-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), aggregation, and even immune activation, have been proposed [4,5,[10][11][12][13]. It has been demonstrated that longer hinges are important in the phagocytic activity of IgG1 and IgG3 isotypes, but not for ADCC or neutralization [14]. ...
Broadly neutralizing antibodies (bNAbs) offer promising opportunities for preventing HIV-1 infection. The protection mechanisms of bNAbs involve the Fc domain, as well as their Fab counterpart. Here, different bNAb isotypes including IgG1, IgA1, IgA2, and IgA122 (IgA2 with the hinge of IgA1) were generated and then produced in CHO cells. Their ability to neutralize pseudovirus and primary HIV-1 isolates were measured, as well as their potential ADCC-like activity using a newly developed assay. In our work, gp41-specific IgA seems to be more efficient than IgG1 in inducing ADCC-like activity, but not in its virus neutralization effect. We show that either gp120-specific IgA or IgG1 isotypes are both efficient in neutralizing different viral strains. In contrast, gp120-specific IgG1 was a better ADCC-like inducer than IgA isotypes. These results provide new insights into the neutralization and ADCC-like activity of different bNAbs that might be taken into consideration when searching for new treatments or antibody-based vaccines.
... Virosomes, another category of virus-derived particles, are liposome-like NPs-phospholipid-bilayered vesicles with virus-derived surface glycoproteins and removed nucleocapsids [129,153,154]. Two unique influenza envelope proteins, haemagglutinin and neuraminidase, are important for virosome reconstitution and endow virosomes with excellent adjuvant properties for the production of various vaccines [154,155]. ...
... Virosomes, another category of virus-derived particles, are liposome-like NPs-phospholipid-bilayered vesicles with virus-derived surface glycoproteins and removed nucleocapsids [129,153,154]. Two unique influenza envelope proteins, haemagglutinin and neuraminidase, are important for virosome reconstitution and endow virosomes with excellent adjuvant properties for the production of various vaccines [154,155]. Virosomes can be modified by different types of antigen epitopes and can target different kinds of host cells [156]. Virosome-based vaccine delivery systems have been successfully developed against hepatitis A viruses and influenza viruses, but in vivo applications are limited due to their high immunogenicity [129]. ...
Undesirable side effects and multidrug resistance are the major obstacles in conventional chemotherapy towards cancers. Nanomedicines provide alternative strategies for tumor-targeted therapy due to their inherent properties, such as nanoscale size and tunable surface features. However , the applications of nanomedicines are hampered in vivo due to intrinsic disadvantages, such as poor abilities to cross biological barriers and unexpected off-target effects. Fortunately, biomi-metic nanomedicines are emerging as promising therapeutics to maximize anti-tumor efficacy with minimal adverse effects due to their good biocompatibility and high accumulation abilities. These bioengineered agents incorporate both the physicochemical properties of diverse functional materials and the advantages of biological materials to achieve desired purposes, such as prolonged circulation time, specific targeting of tumor cells, and immune modulation. Among biological materials , mammalian cells (such as red blood cells, macrophages, monocytes, and neutrophils) and pathogens (such as viruses, bacteria, and fungi) are the functional components most often used to confer synthetic nanoparticles with the complex functionalities necessary for effective nano-biointerac-tions. In this review, we focus on recent advances in the development of bioinspired and biomimetic nanomedicines (such as mammalian cell-based drug delivery systems and pathogen-based nano-particles) for targeted cancer therapy. We also discuss the biological influences and limitations of synthetic materials on the therapeutic effects and targeted efficacies of various nanomedicines.
