Mitigating Covid-19 in the face of emerging virus variants, breakthrough infections and vaccine hesitancy.

The emergence and rapid global spread of the new Delta and, more recently, Omicron variants of SARS-CoV-2 pose a daunting public health emergency. Being an RNA virus, the Covid-19 virus is continuing to mutate, resulting in the emergence of new variants with high transmissibility, such as the recently discovered Omicron variant. In this paper, we consider the conditions that may facilitate viral mutations and the emergence of variants with the ability to evade immunity. Here, we have discussed the importance of vaccination with the currently available vaccines. These vaccines are highly effective at preventing serious disease, hospitalization, and death from Covid-19. However, the antibody response induced by these vaccines is short-lasting and there are reports of breakthrough infections. A stable and persistent interaction between T follicular helper cells and germinal center B cells is needed for robust B cell memory response. We discussed the potential reasons behind the breakthrough infections and underscored the importance of developing better second-generation vaccines that may not necessitate frequent booster immunizations and are preventive in nature. This may involve the development of multivalent vaccines and creating vaccines against other viral proteins including conserved proteins. Vaccine hesitancy remains a notable hurdle for implementing vaccination. Furthermore, we recommend different approaches to increase vaccine acceptance, which is a critical translational component of a successful vaccine strategy. These perspectives on overcoming the pandemic's current challenges provide strategies to contain SARS-CoV-2 globally.

Long Covid: Untangling the Complex Syndrome and the Search for Therapeutics.

Long Covid can affect anyone who has previously had acute COVID-19. The root causes of this syndrome are still unknown, and no effective therapeutics are available. This complex syndrome, with a wide array of symptoms, is still evolving. Given the dire situation, it is important to identify the causes of Long Covid and the changes occurring within the immune system of affected patients to figure out how to treat it. The immune system intersects with the persistent viral fragments and blood clots that are implicated in this syndrome; understanding how these complex systems interact may help in untangling the puzzling physiopathology of Long Covid and identifying mitigation measures to provide patients some relief. In this paper, we discuss evidence-based findings and formulate hypotheses on the mechanisms underlying Long Covid's physiopathology and propose potential therapeutic options.

Efforts at COVID-19 Vaccine Development: Challenges and Successes.

The rapid spread of SARS-CoV-2, the new coronavirus (CoV), throughout the globe poses a daunting public health emergency. Different preventive efforts have been undertaken in response to this global health predicament; amongst them, vaccine development is at the forefront. Several sophisticated designs have been applied to create a vaccine against SARS-CoV-2, and 44 candidates have already entered clinical trials. At present, it is unclear which ones will meet the objectives of efficiency and safety, though several vaccines are gearing up to obtain emergency approval in the U.S. and Europe. This manuscript discusses the advantages and disadvantages of various vaccine platforms and evaluates the safety and efficacy of vaccines in advance stages. Once a vaccine is developed, the next challenge will be acquisition, deployment, and uptake. The present manuscript describes these challenges in detail and proposes solutions to the vast array of translational challenges. It is evident from the epidemiology of SARS-CoV-2 that the virus will remain a threat to everybody as long as the virus is still circulating in a few. We need affordable vaccines that are produced in sufficient quantity for use in every corner of the world.

Eliminating Cervical Cancer in Mali and Senegal, Two Sub-Saharan Countries: Insights and Optimizing Solutions.

BACKGROUND: The number of cases with cervical cancer is rapidly increasing in Sub-Saharan Africa driven by inadequate rates of human papilloma virus (HPV) vaccination and screening programs and accompanied by poor health delivery systems. There are other factors to contend with such as lack of awareness, social myths, reluctance to vaccine acceptance and stigma with sexually transmitted diseases. Here, we formulate strategies to implement intervention programs against HPV infections and other risk factors for cervical cancer in these countries. METHODS: We searched PubMed, Web of Science, and African Journals Online for this review. The current status of anti-HPV vaccination and precancerous screening programs in Mali and Senegal has been assessed by onsite visits. Collaborators from Mali and Senegal collected data and information concerning HPV vaccination and screening programs in these countries. FINDINGS: We found that anti-HPV vaccination and cervical cancer screening have been conducted sporadically mainly in urban areas of Mali and Senegal. No known population-based programs are in progress in either of the two countries. We highlighted the advantages and drawbacks of currently available screening tests and proposed that screening by visual inspection with acetic acid (VIA) accompanied by self-sampling is the most cost-effective, culturally acceptable and most feasible strategy to implement in primary care settings. In addition, HPV DNA testing would be affordable, if local laboratory facilities could be established. We found that many of the factors that increase HPV acquisition and promote the oncogenic effect of the virus are largely widespread in both Senegal and Mali. These include infections with HIV and other sexually transmitted infections (STIs), immunosuppression, polygamous marriages, high parity, early sexual activities, early pregnancies, and multiple sexual partners. INTERPRETATION: Neither vaccines nor screening tests are within the reach of the population in Mali and Senegal because of the high cost. The effective intervention measure would be to integrate anti-HPV vaccines into the Extended Program for Immunization (EPI), which has saved 3 million young lives per year in Africa with the support of GAVI, to implement cost control mechanisms for HPV vaccinations via price negotiations with manufacturing companies, as has recently been done by Rwanda. The collective efforts by local governments, researchers, private sector, and donors may lead to the introduction of affordable screening tests. A robust awareness campaign coupled with sustained and regular engagement of local communities about the prevention and risk factors is extremely important. The projected solutions may be well applicable to other Sub-Saharan countries that face similar challenges containing cervical cancer.

A review of Zika virus: hurdles toward vaccine development and the way forward.

The Zika virus (ZIKV) epidemic has recently emerged as a public health threat due to its teratogenic nature and association with the serious neurological condition Guillain-Barré syndrome (GBS). To date, no approved antiviral therapeutics to treat, nor vaccines to prevent, ZIKV infection are available. In order to develop effective anti-ZIKV vaccines, improved animal models and a better understanding of immunological correlates of protection against ZIKV are required. In this paper, we discuss the recent progress in developing vaccines against ZIKV and the hurdles to overcome in making efficacious anti-ZIKV vaccines. Here, we propose strategies to make efficacious and safe vaccines against ZIKV by using novel approaches including molecular attenuation of viruses and TLR-based nanoparticle vaccines. The question of exacerbating dengue virus infection or causing GBS through the production of cross-reactive immunity targeting viral or host proteins have been addressed in this paper. Challenges in implementing immunogenic and protective ZIKV vaccine trials in immunodepressed target populations (for example, pregnant women) have also been discussed.

CD4+ T cells from multiple sclerosis patients respond to a commensal-derived antigen.

Multiple sclerosis, an immune-mediated disease of the central nervous system, is characterized by the impaired function of regulatory cells that fail to suppress self-reactive effector cells. We have previously found that polysaccharide A, a capsular antigen derived from the human gut commensal Bacteroides fragilis, can induce a population of regulatory T cells. Herein, we demonstrate that naïve T cells isolated from patients with multiple sclerosis have the capacity to acquire regulatory characteristics when stimulated in vitro with polysaccharide A. This study demonstrates the amplification of a regulatory T cell response by a gut-derived commensal antigen in those with multiple sclerosis.

Alteration of CD39+Foxp3+ CD4 T cell and cytokine levels in EAE/MS following anti-CD52 treatment.

While examining the therapeutic value of anti-CD52 antibody against EAE/MS, we identified a unique subset of CD39+ Tregs in repopulating GALT tissues, a major lymphoid reservoir, which was accompanied by amelioration of disease. Furthermore, anti-CD52 treatment leads to increased expression of BDNF, IL-10, and SMAD3 in the brains of EAE mice. This condition is associated with suppression of IL-17, a critical inflammatory factor in EAE/MS progression. Additionally, we found elevated levels of CD4+CD39+ Tregs in PBMCs of RRMS patients treated with humanized anti-CD52 mAb. Thus, anti-CD52 can affect multiple immune mediated pathways involved in the pathogenesis of EAE/MS.

Induction of gut regulatory CD39+ T cells by teriflunomide protects against EAE.

OBJECTIVE: To determine whether as an orally delivered treatment, teriflunomide, an inhibitor of the mitochondrial enzyme dihydroorotate dehydrogenase approved to treat relapsing forms of multiple sclerosis, could affect gut-associated lymphoid tissue (GALT) immune responses functionally. METHODS: C57BL/6 mice were treated orally with teriflunomide and flow cytometric analysis of immune GALT cells performed ex vivo, and adoptive transfer experiments were used to test the protective effects of GALT regulatory T (Treg) cells. RESULTS: Teriflunomide reduced the percentages of antigen-presenting cells of Peyer patches when compared to controls. Conversely, a significant increase of the relative frequency of CD39+ Treg cells was observed. In vivo, the protective effect of GALT-derived teriflunomide-induced CD39+ Treg cells was established by adoptive transfer into recipient experimental autoimmune encephalomyelitis mice. CONCLUSIONS: Our results identify specific GALT-derived CD39+ Treg cells as a mechanism of action that may contribute to the efficacy of teriflunomide during CNS inflammatory demyelination and as an oral therapeutic in relapsing multiple sclerosis.

A commensal symbiotic factor derived from Bacteroides fragilis promotes human CD39(+)Foxp3(+) T cells and Treg function.

Polysaccharide A (PSA) derived from the human commensal Bacteroides fragilis is a symbiosis factor that stimulates immunologic development within mammalian hosts. PSA rebalances skewed systemic T helper responses and promotes T regulatory cells (Tregs). However, PSA-mediated induction of Foxp3 in humans has not been reported. In mice, PSA-generated Foxp3(+) Tregs dampen Th17 activity thereby facilitating bacterial intestinal colonization while the increased presence and function of these regulatory cells may guard against pathological organ-specific inflammation in hosts. We herein demonstrate that PSA induces expression of Foxp3 along with CD39 among naïve CD4 T cells in vitro while promoting IL-10 secretion. PSA-activated dendritic cells are essential for the mediation of this regulatory response. When cultured with isolated Foxp3(+) Tregs, PSA enriched Foxp3 expression, enhanced the frequency of CD39(+)HLA-DR(+) cells, and increased suppressive function as measured by decreased TNFα expression by LPS-stimulated monocytes. Our findings are the first to demonstrate in vitro induction of human CD4(+)Foxp3(+) T cells and enhanced suppressive function of circulating Foxp3(+) Tregs by a human commensal bacterial symbiotic factor. Use of PSA for the treatment of human autoimmune diseases, in particular multiple sclerosis and inflammatory bowel disease, may represent a new paradigm in the approach to treating autoimmune disease.