Design, Immunogenicity and Preclinical Efficacy of the ChAdOx1.COVconsv12 Pan-Sarbecovirus T-Cell Vaccine.

During the COVID-19 pandemic, antibody-based vaccines targeting the SARS-CoV-2 spike glycoprotein were the focus for development because neutralizing antibodies were associated with protection against the SARS-CoV-2 infection pre-clinically and in humans. While deploying these spike-based vaccines saved millions of lives worldwide, it has become clear that the immunological mechanisms of protection against severe disease are multifaceted and involve non-neutralizing antibody components. Here, we describe a novel pan-sarbecovirus T-cell vaccine, ChAdOx1.COVconsv12, designed to complement and broaden the protection of spike vaccines. The vaccine immunogen COVconsv12 employs the two regions in the viral proteome most conserved among sarbecoviruses, which are delivered by replication-deficient vector ChAdOx1. It directs T cells towards epitopes shared among sarbecoviruses including evolving SARS-CoV-2 variants. Here, we show that ChAdOx1.COVconsv12 induced broad T-cell responses in the BALB/c and C57BL/6 mice. In the Syrian hamster challenge model, ChAdOx1.COVconsv12 alone did not protect against the SARS-CoV-2 infection, but when co-administered with 1/50th of the ChAdOx1 nCoV-19 spike vaccine protective dose, faster recovery and lower oral swab viral load were observed. Induction of CD8+ T cells may decrease COVID-19 severity and extend the T-cell response coverage of variants to match the known (and as yet unknown) members of the ß-coronavirus family.

Impact of ChAdOx1 or DNA Prime Vaccination on Magnitude, Breadth, and Focus of MVA-Boosted Immunogen-Specific T Cell Responses.

The efficacy of anti-viral T-cell vaccines may greatly depend on their ability to generate high-magnitude responses targeting a broad range of different epitopes. Recently, we created the HIV T-cell immunogen HTI, designed to generate T-cell responses to protein fragments more frequently targeted by HIV controllers. In the present study, we aim to maximize the breadth and magnitude of the T-cell responses generated by HTI by combining different vaccine vectors expressing HTI. We evaluated the ability to induce strong and broad T-cell responses to the HTI immunogen through prime vaccination with DNA plasmid (D) or Chimpanzee Adenovirus Ox1 (ChAdOx1; C) vectors, followed by a Modified Virus Ankara (MVA; M) vaccine boost (DDD, DDDM, C, and CM). HTI-specific T-cell responses after vaccination were measured by IFN-γ-ELISpot assays in two inbred mice strains (C57BL/6 and BALB/c). CM was the schedule triggering the highest magnitude of the response in both mice strains. However, this effect was not reflected in an increase in the breadth of the response but rather in an increase in the magnitude of the response to specific immunodominant epitopes. Immunodominance profiles in the two mouse strains were different, with a clear dominance of T-cell responses to a Pol-derived peptide pool after CM vaccination in C57BL/6. Responses to CM vaccination were also maintained at higher magnitudes over time (13 weeks) compared to other vaccination regimens. Thus, while a ChAdOx1 prime combined with MVA booster vaccination generated stronger and more sustained T-cell responses compared to three DNA vaccinations, the ChAdOx1 primed responses were more narrowly targeted. In conclusion, our findings suggest that the choice of vaccine vectors and prime-boost regimens plays a crucial role in determining the strength, duration, breadth, and focus of T-cell responses, providing further guidance for selecting vaccination strategies.

Preclinical proof of concept of a tetravalent lentiviral T-cell vaccine against dengue viruses.

Dengue virus (DENV) is responsible for approximately 100 million cases of dengue fever annually, including severe forms such as hemorrhagic dengue and dengue shock syndrome. Despite intensive vaccine research and development spanning several decades, a universally accepted and approved vaccine against dengue fever has not yet been developed. The major challenge associated with the development of such a vaccine is that it should induce simultaneous and equal protection against the four DENV serotypes, because past infection with one serotype may greatly increase the severity of secondary infection with a distinct serotype, a phenomenon known as antibody-dependent enhancement (ADE). Using a lentiviral vector platform that is particularly suitable for the induction of cellular immune responses, we designed a tetravalent T-cell vaccine candidate against DENV ("LV-DEN"). This vaccine candidate has a strong CD8+ T-cell immunogenicity against the targeted non-structural DENV proteins, without inducing antibody response against surface antigens. Evaluation of its protective potential in the preclinical flavivirus infection model, i.e., mice knockout for the receptor to the type I IFN, demonstrated its significant protective effect against four distinct DENV serotypes, based on reduced weight loss, viremia, and viral loads in peripheral organs of the challenged mice. These results provide proof of concept for the use of lentiviral vectors for the development of efficient polyvalent T-cell vaccine candidates against all DENV serotypes.

The T-cell-directed vaccine BNT162b4 encoding conserved non-spike antigens protects animals from severe SARS-CoV-2 infection.

T cell responses play an important role in protection against beta-coronavirus infections, including SARS-CoV-2, where they associate with decreased COVID-19 disease severity and duration. To enhance T cell immunity across epitopes infrequently altered in SARS-CoV-2 variants, we designed BNT162b4, an mRNA vaccine component that is intended to be combined with BNT162b2, the spike-protein-encoding vaccine. BNT162b4 encodes variant-conserved, immunogenic segments of the SARS-CoV-2 nucleocapsid, membrane, and ORF1ab proteins, targeting diverse HLA alleles. BNT162b4 elicits polyfunctional CD4+ and CD8+ T cell responses to diverse epitopes in animal models, alone or when co-administered with BNT162b2 while preserving spike-specific immunity. Importantly, we demonstrate that BNT162b4 protects hamsters from severe disease and reduces viral titers following challenge with viral variants. These data suggest that a combination of BNT162b2 and BNT162b4 could reduce COVID-19 disease severity and duration caused by circulating or future variants. BNT162b4 is currently being clinically evaluated in combination with the BA.4/BA.5 Omicron-updated bivalent BNT162b2 (NCT05541861).

DNA immunization with in silico predicted T-cell epitopes protects against lethal SARS-CoV-2 infection in K18-hACE2 mice.

The global SARS-CoV-2 pandemic caused significant social and economic disruption worldwide, despite highly effective vaccines being developed at an unprecedented speed. Because the first licensed vaccines target only single B-cell antigens, antigenic drift could lead to loss of efficacy against emerging SARS-CoV-2 variants. Improving B-cell vaccines by including multiple T-cell epitopes could solve this problem. Here, we show that in silico predicted MHC class I/II ligands induce robust T-cell responses and protect against severe disease in genetically modified K18-hACE2/BL6 mice susceptible to SARS-CoV-2 infection.

A pan-variant mRNA-LNP T cell vaccine protects HLA transgenic mice from mortality after infection with SARS-CoV-2 Beta.

Licensed COVID-19 vaccines ameliorate viral infection by inducing production of neutralizing antibodies that bind the SARS-CoV-2 Spike protein and inhibit viral cellular entry. However, the clinical effectiveness of these vaccines is transitory as viral variants escape antibody neutralization. Effective vaccines that solely rely upon a T cell response to combat SARS-CoV-2 infection could be transformational because they can utilize highly conserved short pan-variant peptide epitopes, but a mRNA-LNP T cell vaccine has not been shown to provide effective anti-SARS-CoV-2 prophylaxis. Here we show a mRNA-LNP vaccine (MIT-T-COVID) based on highly conserved short peptide epitopes activates CD8+ and CD4+ T cell responses that attenuate morbidity and prevent mortality in HLA-A*02:01 transgenic mice infected with SARS-CoV-2 Beta (B.1.351). We found CD8+ T cells in mice immunized with MIT-T-COVID vaccine significantly increased from 1.1% to 24.0% of total pulmonary nucleated cells prior to and at 7 days post infection (dpi), respectively, indicating dynamic recruitment of circulating specific T cells into the infected lungs. Mice immunized with MIT-T-COVID had 2.8 (2 dpi) and 3.3 (7 dpi) times more lung infiltrating CD8+ T cells than unimmunized mice. Mice immunized with MIT-T-COVID had 17.4 times more lung infiltrating CD4+ T cells than unimmunized mice (7 dpi). The undetectable specific antibody response in MIT-T-COVID-immunized mice demonstrates specific T cell responses alone can effectively attenuate the pathogenesis of SARS-CoV-2 infection. Our results suggest further study is merited for pan-variant T cell vaccines, including for individuals that cannot produce neutralizing antibodies or to help mitigate Long COVID.

CpG 1018 Is an Effective Adjuvant for Influenza Nucleoprotein.

Current influenza vaccines mainly induce neutralizing antibodies against the highly variable surface antigen hemagglutinin and require annual manufacturing and immunization. Different from surface antigens, intracellular nucleoprotein (NP) is highly conserved and has been an attractive target to develop universal T cell vaccines against influenza. Yet, influenza NP protein mainly induces humoral immune responses and lacks the ability to induce potent cytotoxic T lymphocyte (CTL) responses, key for the success of universal T cell vaccines. This study compared CpG 1018 and AddaVax to enhance recombinant NP-induced CTL responses and protection in murine models. CpG 1018 was explored to boost intradermal NP immunization, while AddaVax was explored to boost intramuscular NP immunization due to the high risk of AddaVax adjuvant to induce significant local reactions following intradermal delivery. We found CpG 1018 was highly effective to enhance NP-induced humoral and cellular immune responses superior to AddaVax adjuvant. Furthermore, CpG 1018 potentiated Th1-biased antibody responses, while AddaVax enhanced Th1/Th2-balanced antibody responses. CpG 1018 significantly enhanced IFNγ-secreting Th1 cells, while AddaVax adjuvant significantly increased IL4-secreting Th2 cells. Influenza NP immunization in the presence of CpG 1018 induced significant protection against lethal viral challenges, while influenza NP immunization in the presence of AddaVax failed to elicit significant protection. Our data validated CpG 1018 as an effective adjuvant to enhance influenza NP-induced CTL responses and protection.

Evaluation of a Human T Cell-Targeted Multi-Epitope Vaccine for Q Fever in Animal Models of Coxiella burnetii Immunity.

T cell-mediated immunity plays a central role in the control and clearance of intracellular Coxiella burnetii infection, which can cause Q fever. Therefore, we aimed to develop a novel T cell-targeted vaccine that induces pathogen-specific cell-mediated immunity to protect against Q fever in humans while avoiding the reactogenicity of the current inactivated whole cell vaccine. Human HLA class II T cell epitopes from C. burnetii were previously identified and selected by immunoinformatic predictions of HLA binding, conservation in multiple C. burnetii isolates, and low potential for cross-reactivity with the human proteome or microbiome. Epitopes were selected for vaccine inclusion based on long-lived human T cell recall responses to corresponding peptides in individuals that had been naturally exposed to the bacterium during a 2007-2010 Q fever outbreak in the Netherlands. Multiple viral vector-based candidate vaccines were generated that express concatemers of selected epitope sequences arranged to minimize potential junctional neo-epitopes. The vaccine candidates caused no antigen-specific reactogenicity in a sensitized guinea pig model. A subset of the vaccine epitope peptides elicited antigenic recall responses in splenocytes from C57BL/6 mice previously infected with C. burnetii. However, immunogenicity of the vaccine candidates in C57BL/6 mice was dominated by a single epitope and this was insufficient to confer protection against an infection challenge, highlighting the limitations of assessing human-targeted vaccine candidates in murine models. The viral vector-based vaccine candidates induced antigen-specific T cell responses to a broader array of epitopes in cynomolgus macaques, establishing a foundation for future vaccine efficacy studies in this large animal model of C. burnetii infection.

Cytotoxic T-Cell-Based Vaccine against SARS-CoV-2: A Hybrid Immunoinformatic Approach.

This paper presents an alternative vaccination platform that provides long-term cellular immune protection mediated by cytotoxic T-cells. The immune response via cellular immunity creates superior resistance to viral mutations, which are currently the greatest threat to the global vaccination campaign. Furthermore, we also propose a safer, more facile, and physiologically appropriate immunization method using either intranasal or oral administration. The underlying technology is an adaptation of synthetic long peptides (SLPs) previously used in cancer immunotherapy. The overall quality of the SLP constructs was validated using in silico methods. SLPs comprising HLA class I and class II epitopes were designed to stimulate antigen cross-presentation and canonical class II presentation by dendritic cells. The desired effect is a cytotoxic T cell-mediated prompt and specific immune response against the virus-infected epithelia and a rapid and robust virus clearance. Epitopes isolated from COVID-19 convalescent patients were screened for HLA class I and class II binding (NetMHCpan and NetMHCIIpan) and highest HLA population coverage (IEDB Population Coverage). 15 class I and 4 class II epitopes were identified and used for this SLP design. The constructs were characterized based on their toxicity (ToxinPred), allergenicity (AllerCatPro), immunogenicity (VaxiJen 2.0), and physico-chemical parameters (ProtParam). Based on in silico predictions, out of 60 possible SLPs, 36 candidate structures presented a high probability to be immunogenic, non-allergenic, non-toxic, and stable. 3D peptide folding followed by 3D structure validation (PROCHECK) and molecular docking studies (HADDOCK 2.4) with Toll-like receptors 2 and 4 provided positive results, suggestive for favorable antigen presentation and immune stimulation.

T cells protect against hepatitis A virus infection and limit infection-induced liver injury.

BACKGROUND & AIMS: Hepatitis A virus (HAV) is a common cause of enterically transmitted viral hepatitis. In non-immune individuals, infection results in typically transient but occasionally fulminant and fatal inflammatory liver injury. Virus-specific T cell frequencies peak when liver damage is at its zenith, leading to the prevalent notion that T cells exacerbate liver disease, as suspected for other hepatotropic virus infections. However, the overall contribution of T cells to the control of HAV and the pathogenesis of hepatitis A is unclear and has been impeded by a historic lack of small animal models. METHODS: Ifnar1-/- mice are highly permissive for HAV and develop pathogenesis that recapitulates many features of hepatitis A. Using this model, we identified HAV-specific CD8+ and CD4+ T cells by epitope mapping, and then used tetramers and functional assays to quantify T cells in the liver at multiple times after infection. We assessed the relationships between HAV-specific T cell frequency, viral RNA amounts, and liver pathogenesis. RESULTS: A large population of virus-specific T cells accumulated within the livers of Ifnar1-/- mice during the first 1-2 weeks of infection and persisted over time. HAV replication was enhanced and liver disease exacerbated when mice were depleted of T cells. Conversely, immunization with a peptide vaccine increased virus-specific CD8+ T cell frequencies in the liver, reduced viral RNA abundance, and lessened liver injury. CONCLUSION: These data show that T cells protect against HAV-mediated liver injury and can be targeted to improve liver health. LAY SUMMARY: Hepatitis A virus is a leading cause of acute viral hepatitis worldwide. T cells were thought to contribute to liver injury during acute infection. We now show that virus-specific T cells protect against infection and limit liver injury.

Effect of epitope variant co-delivery on the depth of CD8 T cell responses induced by HIV-1 conserved mosaic vaccines.

To stop the HIV-1 pandemic, vaccines must induce responses capable of controlling vast HIV-1 variants circulating in the population as well as those evolved in each individual following transmission. Numerous strategies have been proposed, of which the most promising include focusing responses on the vulnerable sites of HIV-1 displaying the least entropy among global isolates and using algorithms that maximize vaccine match to circulating HIV-1 variants by vaccine cocktails of optimized complementing sequences. In this study, we investigated CD8 T cell responses induced by a bi-valent mosaic of highly conserved HIVconsvX regions delivered by a combination of simian adenovirus ChAdOx1 and poxvirus MVA. We compared partially and fully mono- and bi-valent prime-boost regimens and their ability to elicit T cells recognizing natural epitope variants using an interferon-γ enzyme-linked immunospot (ELISPOT) assay. We used 11 well-defined CD8 T cell epitopes in two mouse haplotypes and, for each epitope, assessed recognition of the two vaccine forms together with the other most frequent epitope variants in the HIV-1 database. We conclude that for the magnitude and depth of epitope recognition, CD8 T cell responses benefitted in most comparisons from the combined bi-valent mosaic and envisage the main advantage of the bi-valent vaccine during its deployment to diverse populations.

Robust induction of TRMs by combinatorial nanoshells confers cross-strain sterilizing immunity against lethal influenza viruses.

Antigen-specific lung-resident memory T cells (TRMs) constitute the first line of defense that mediates rapid protection against respiratory pathogens and inspires novel vaccine designs against infectious pandemic threats, yet effective means of inducing TRMs, particularly via non-viral vectors, remain challenging. Here, we demonstrate safe and potent induction of lung-resident TRMs using a biodegradable polymeric nanoshell that co-encapsulates antigenic peptides and TLR9 agonist CpG-oligodeoxynucleotide (CpG-ODN) in a virus-mimicking structure. Through subcutaneous priming and intranasal boosting, the combinatorial nanoshell vaccine elicits prominent lung-resident CD4+ and CD8+ T cells that surprisingly show better durability than live viral infections. In particular, nanoshells containing CpG-ODN and a pair of conserved class I and II major histocompatibility complex-restricted influenza nucleoprotein-derived antigenic peptides are demonstrated to induce near-sterilizing immunity against lethal infections with influenza A viruses of different strains and subtypes in mice, resulting in rapid elimination of replicating viruses. We further examine the pulmonary transport dynamic and optimal composition of the nanoshell vaccine conducive for robust TRM induction as well as the benefit of subcutaneous priming on TRM replenishment. The study presents a practical vaccination strategy for inducing protective TRM-mediated immunity, offering a compelling platform and critical insights in the ongoing quest toward a broadly protective vaccine against universal influenza as well as other respiratory pathogens.

Sampling SARS-CoV-2 Proteomes for Predicted CD8 T-Cell Epitopes as a Tool for Understanding Immunogenic Breadth and Rational Vaccine Design.

Predictive models for vaccine design have become a powerful and necessary resource for the expeditiousness design of vaccines to combat the ongoing SARS-CoV-2 global pandemic. Here we use the power of these predicted models to assess the sequence diversity of circulating SARS-CoV-2 proteomes in the context of an individual's CD8 T-cell immune repertoire to identify potential. defined regions of immunogenicity. Using this approach of expedited and rational CD8 T-cell vaccine design, it may be possible to develop a therapeutic vaccine candidate with the potential for both global and local coverage.

Non invasive in vivo monitoring of dimethyl fumarate treatment in EAE by assessing the glucose metabolism in secondary lymphoid organs.

[18 F]FDG-PET/CT is a high sensitive functional diagnostic imaging modality to monitor tumor but also immune cell activation by determination of the glucose metabolism. Our results show that the anti-inflammatory effects of immunotherapeutics like DMF can be assessed non invasively in vivo during Th1/Th17 cell-mediated encephalomyelitis (EAE) by [18 F]FDG-PET/CT imaging of the draining lymph nodes.

Dexamethasone premedication suppresses vaccine-induced immune responses against cancer.

Glucocorticosteroids (GCS) have an established role in oncology and are administered to cancer patients in routine clinical care and in drug development trials as co-medication. Given their strong immune-suppressive activity, GCS may interfere with immune-oncology drugs. We are developing a therapeutic cancer vaccine, which is based on a liposomal formulation of tumor-antigen encoding RNA (RNA-LPX) and induces a strong T-cell response both in mice as well as in humans. In this study, we investigated in vivo in mice and in human PBMCs the effect of the commonly used long-acting GCS Dexamethasone (Dexa) on the efficacy of this vaccine format, with a particular focus on antigen-specific T-cell immune responses. We show that Dexa, when used as premedication, substantially blunts RNA-LPX vaccine-mediated immune effects. Premedication with Dexa inhibits vaccine-dependent induction of serum cytokines and chemokines and reduces both the number and activation of splenic conventional dendritic cells (cDC) expressing vaccine-encoded antigens. Consequently, priming of functional effector T cells and therapeutic activity is significantly impaired. Interestingly, responses are less impacted when Dexa is administered post-vaccination. Consistent with this observation, although many inflammatory cytokines are reduced, IFNα, a key cytokine in T-cell priming, is less impacted and antigen expression by cDCs is intact. These findings warrant special caution when combining GCS with immune therapies relying on priming and activation of antigen-specific T cells and suggest that careful sequencing of these treatments may preserve T-cell induction.

Tetravalent Immunogen Assembled from Conserved Regions of HIV-1 and Delivered as mRNA Demonstrates Potent Preclinical T-Cell Immunogenicity and Breadth.

A vaccine will likely be one of the key tools for ending the HIV-1/AIDS epidemic by preventing HIV-1 spread within uninfected populations and achieving a cure for people living with HIV-1. The currently prevailing view of the vaccine field is to introduce protective antibodies, nevertheless, a vaccine to be effective may need to harness protective T cells. We postulated that focusing a T-cell response on the most vulnerable regions of the HIV-1 proteome while maximizing a perfect match between the vaccine and circulating viruses will control HIV-1 replication. We currently use a combination of replication-deficient simian (chimpanzee) adenovirus and poxvirus modified vaccinia virus Ankara to deliver bivalent conserved-mosaic immunogens to human volunteers. Here, we exploit the mRNA platform by designing tetravalent immunogens designated as HIVconsvM, and demonstrate that mRNA formulated in lipid nanoparticles induces potent, broad and polyfunctional T-cell responses in a pre-clinical model. These results support optimization and further development of this vaccine strategy in experimental medicine trials in humans.

Specificity of CD8+ T-Cell Responses Following Vaccination with Conserved Regions of HIV-1 in Nairobi, Kenya.

Sub-Saharan Africa carries the biggest burden of the human immunodeficiency virus type 1 (HIV-1)/AIDS epidemic and is in an urgent need of an effective vaccine. CD8+ T cells are an important component of the host immune response to HIV-1 and may need to be harnessed if a vaccine is to be effective. CD8+ T cells recognize human leukocyte antigen (HLA)-associated viral epitopes and the HLA alleles vary significantly among different ethnic groups. It follows that definition of HIV-1-derived peptides recognized by CD8+ T cells in the geographically relevant regions will critically guide vaccine development. Here, we study fine details of CD8+ T-cell responses elicited in HIV-1/2-uninfected individuals in Nairobi, Kenya, who received a candidate vaccine delivering conserved regions of HIV-1 proteins called HIVconsv. Using 10-day cell lines established by in vitro peptide restimulation of cryopreserved PBMC and stably HLA-transfected 721.221/C1R cell lines, we confirm experimentally many already defined epitopes, for a number of epitopes we define the restricting HLA molecule(s) and describe four novel HLA-epitope pairs. We also identify specific dominance patterns, a promiscuous T-cell epitope and a rescue of suboptimal T-cell epitope induction in vivo by its functional variant, which all together inform vaccine design.

The Design and Development of a Multi-HBV Antigen Encoded in Chimpanzee Adenoviral and Modified Vaccinia Ankara Viral Vectors; A Novel Therapeutic Vaccine Strategy against HBV.

Chronic hepatitis B virus (HBV) infection affects 257 million people globally. Current therapies suppress HBV but viral rebound occurs on cessation of therapy; novel therapeutic strategies are urgently required. To develop a therapeutic HBV vaccine that can induce high magnitude T cells to all major HBV antigens, we have developed a novel HBV vaccine using chimpanzee adenovirus (ChAd) and modified vaccinia Ankara (MVA) viral vectors encoding multiple HBV antigens. ChAd vaccine alone generated very high magnitude HBV specific T cell responses to all HBV major antigens. The inclusion of a shark Invariant (SIi) chain genetic adjuvant significantly enhanced the magnitude of T-cells against HBV antigens. Compared to ChAd alone vaccination, ChAd-prime followed by MVA-boost vaccination further enhanced the magnitude and breadth of the vaccine induced T cell response. Intra-cellular cytokine staining study showed that HBV specific CD8+ and CD4+ T cells were polyfunctional, producing combinations of IFNγ, TNF-α, and IL-2. In summary, we have generated genetically adjuvanted ChAd and MVA vectored HBV vaccines with the potential to induce high-magnitude T cell responses through a prime-boost therapeutic vaccination approach. These pre-clinical studies pave the way for new studies of HBV therapeutic vaccination in humans with chronic hepatitis B infection.

Infections, Vaccines and Autoimmunity: A Multiple Sclerosis Perspective.

Background: Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease that is associated with multiple environmental factors. Among suspected susceptibility events, studies have questioned the potential role of overt viral and bacterial infections, including the Epstein Bar virus (EBV) and human endogenous retroviruses (HERV). Furthermore, the fast development of immunomodulatory therapies further questions the efficacy of the standard immunization policies in MS patients. Topics reviewed: This narrative review will discuss the potential interplay between viral and bacterial infections and their treatment on MS susceptibility and disease progression. In addition, the review specifically discusses the interactions between MS pathophysiology and vaccination for hepatitis B, influenza, human papillomavirus, diphtheria, pertussis, and tetanus (DTP), and Bacillus Calmette-Guerin (BCG). Data regarding potential interaction between MS disease modifying treatment (DMT) and vaccine effectiveness is also reviewed. Moreover, HERV-targeted therapies such as GNbAC1 (temelimab), EBV-based vaccines for treatment of MS, and the current state regarding the development of T-cell and DNA vaccination are discussed. Lastly, a reviewing commentary on the recent 2019 American Academy of Neurology (AAN) practice recommendations regarding immunization and vaccine-preventable infections in the settings of MS is provided. Conclusion: There is currently no sufficient evidence to support associations between standard vaccination policies and increased risk of MS. MS patients treated with immunomodulatory therapies may have a lower benefit from viral and bacterial vaccination. Despite their historical underperformance, new efforts in creating MS-based vaccines are currently ongoing. MS vaccination programs follow the set back and slow recovery which is widely seen in other fields of medicine.

Novel Nested Peptide Epitopes Recognized by CD4+ T Cells Induced by HIV-1 Conserved-Region Vaccines.

CD4+ T-cell responses play an important role in the immune control of the human immunodeficiency virus type 1 (HIV-1) infection and as such should be efficiently induced by vaccination. It follows that definition of HIV-1-derived peptides recognized by CD4+ T cells in association with HLA class II molecules will guide vaccine development. Here, we have characterized the fine specificity of CD4+ T cells elicited in human recipients of a candidate vaccine delivering conserved regions of HIV-1 proteins designated HIVconsv. The majority of these 19 most immunogenic regions contained novel epitopes, that is, epitopes not listed in the Los Alamos National Laboratory HIV Sequence Database, which were able in vitro to stimulate vaccinees' CD4+ T cells to proliferate and produce interferon-γ and tumor necrosis factor-α. Accumulation of HLA class II epitopes will eventually accelerate development of HIV-1 prophylactic and therapeutic vaccines.