An Adjuvanted Inactivated SARS-CoV-2 Microparticulate Vaccine Delivered Using Microneedles Induces a Robust Immune Response in Vaccinated Mice.

SARS-CoV-2, the causal agent of COVID-19, is a contagious respiratory virus that frequently mutates, giving rise to variant strains and leading to reduced vaccine efficacy against the variants. Frequent vaccination against the emerging variants may be necessary; thus, an efficient vaccination system is needed. A microneedle (MN) vaccine delivery system is non-invasive, patient-friendly, and can be self-administered. Here, we tested the immune response produced by an adjuvanted inactivated SARS-CoV-2 microparticulate vaccine administered via the transdermal route using a dissolving MN. The inactivated SARS-CoV-2 vaccine antigen and adjuvants (Alhydrogel® and AddaVax™) were encapsulated in poly(lactic-co-glycolic acid) (PLGA) polymer matrices. The resulting MP were approximately 910 nm in size, with a high percentage yield and percent encapsulation efficiency of 90.4%. In vitro, the vaccine MP was non-cytotoxic and increased the immunostimulatory activity measured as nitric oxide release from dendritic cells. The adjuvant MP potentiated the immune response of the vaccine MP in vitro. In vivo, the adjuvanted SARS-CoV-2 MP vaccine induced high levels of IgM, IgG, IgA, IgG1, and IgG2a antibodies and CD4+ and CD8+ T-cell responses in immunized mice. In conclusion, the adjuvanted inactivated SARS-CoV-2 MP vaccine delivered using MN induced a robust immune response in vaccinated mice.

Subunit microparticulate vaccine delivery using microneedles trigger significant SARS-spike-specific humoral and cellular responses in a preclinical murine model.

The objective of this "proof-of-concept" study was to evaluate the synergistic effect of a subunit microparticulate vaccine and microneedles (MN) assisted vaccine delivery system against a human coronavirus. Here, we formulated PLGA polymeric microparticles (MPs) encapsulating spike glycoprotein (GP) of SARS-CoV as the model antigen. Similarly, we formulated adjuvant MPs encapsulating Alhydrogel® and AddaVax™. The antigen/adjuvant MPs were characterized and tested in vitro for immunogenicity. We found that the antigen/adjuvant MPs were non-cytotoxic in vitro. The spike GP MPs + Alhydrogel® MPs + AddaVax™ MPs showed enhanced immunogenicity in vitro as confirmed through the release of nitrite, autophagy, and antigen presenting molecules with their co-stimulatory molecules. Next, we tested the in vivo efficacy of the spike GP MP vaccine with and without adjuvant MPs in mice vaccinated using MN. The spike GP MPs + Alhydrogel® MPs + AddaVax™ MPs induced heightened spike GP-specific IgG, IgG1 and IgG2a antibodies in mice. Also, spike GP MPs + Alhydrogel® MPs + AddaVax™ MPs enhanced expression of CD4+ and CD8+ T cells in secondary lymphoid organ like spleen. These results indicated spike GP-specific humoral immunity and cellular immunity in vivo. Thus, we employed the benefits of both the subunit vaccine MPs and dissolving MN to form a non-invasive and effective vaccination strategy against human coronaviruses.

Microneedle Delivery of an Adjuvanted Microparticulate Vaccine Induces High Antibody Levels in Mice Vaccinated against Coronavirus.

This 'proof-of-concept' study aimed to test the microparticulate vaccine delivery system and a transdermal vaccine administration strategy using dissolving microneedles (MN). For this purpose, we formulated poly(lactic-co-glycolic) acid (PLGA) microparticles (MP) encapsulating the inactivated canine coronavirus (iCCoV), as a model antigen, along with adjuvant MP encapsulating Alhydrogel® and AddaVax. We characterized the vaccine MP for size, surface charge, morphology, and encapsulation efficiency. Further, we evaluated the in vitro immunogenicity, cytotoxicity, and antigen-presentation of vaccine/adjuvant MP in murine dendritic cells (DCs). Additionally, we tested the in vivo immunogenicity of the MP vaccine in mice through MN administration. We evaluated the serum IgG, IgA, IgG1, and IgG2a responses using an enzyme-linked immunosorbent assay. The results indicate that the particulate form of the vaccine is more immunogenic than the antigen suspension in vitro. We found the vaccine/adjuvant MP to be non-cytotoxic to DCs. The expression of antigen-presenting molecules, MHC I/II, and their costimulatory molecules, CD80/40, increased with the addition of the adjuvants. Moreover, the results suggest that the MP vaccine is cross presented by the DCs. In vivo, the adjuvanted MP vaccine induced increased antibody levels in mice following vaccination and will further be assessed for its cell-mediated responses.

A Review on Current COVID-19 Vaccines and Evaluation of Particulate Vaccine Delivery Systems.

First detected in Wuhan, China, a highly contagious coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), also known as COVID-19, spread globally in December of 2019. As of 19 September 2021, approximately 4.5 million people have died globally, and 215 million active cases have been reported. To date, six vaccines have been developed and approved for human use. However, current production and supply capabilities are unable to meet global demands to immunize the entire world population. Only a few countries have been able to successfully vaccinate many of their residents. Therefore, an alternative vaccine that can be prepared in an easy and cost-effective manner is urgently needed. A vaccine that could be prepared in this manner, as well as can be preserved and transported at room temperature, would be of great benefit to public health. It is possible to develop such an alternative vaccine by using nano- or microparticle platforms. These platforms address most of the existing vaccine limitations as they are stable at room temperature, are inexpensive to produce and distribute, can be administered orally, and do not require cold chain storage for transportation or preservation. Particulate vaccines can be administered as either oral solutions or in sublingual or buccal film dosage forms. Besides improved patient compliance, the major advantage of oral, sublingual, and buccal routes of administration is that they can elicit mucosal immunity. Mucosal immunity, along with systemic immunity, can be a strong defense against SARS-CoV-2 as the virus enters the system through inhalation or saliva. This review discusses the possibility to produce a particulate COVID vaccine by using nano- or microparticles as platforms for oral administration or in sublingual or buccal film dosage forms in order to accelerate global vaccination.

Challenges of Storage and Stability of mRNA-Based COVID-19 Vaccines.

In December 2019, a new and highly pathogenic coronavirus emerged-coronavirus disease 2019 (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), quickly spread throughout the world. In response to this global pandemic, a few vaccines were allowed for emergency use, beginning in November 2020, of which the mRNA-based vaccines by Moderna (Moderna, Cambridge, MA, USA) and BioNTech (BioTech, Mainz, Germany)/Pfizer (Pfizer, New York, NY, USA) have been identified as the most effective ones. The mRNA platform allowed rapid development of vaccines, but their global use is limited by ultracold storage requirements. Most resource-poor countries do not have cold chain storage to execute mass vaccination. Therefore, determining strategies to increase stability of mRNA-based vaccines in relatively higher temperatures can be a game changer to address the current global pandemic and upcoming new waves. In this review, we summarized the current research strategies to enhance stability of the RNA vaccine delivery system.

Microneedles: A New Generation Vaccine Delivery System.

Transdermal vaccination route using biodegradable microneedles is a rapidly progressing field of research and applications. The fear of painful needles is one of the primary reasons most people avoid getting vaccinated. Therefore, developing an alternative pain-free method of vaccination using microneedles has been a significant research area. Microneedles comprise arrays of micron-sized needles that offer a pain-free method of delivering actives across the skin. Apart from being pain-free, microneedles provide various advantages over conventional vaccination routes such as intramuscular and subcutaneous. Microneedle vaccines induce a robust immune response as the needles ranging from 50 to 900 µm in length can efficiently deliver the vaccine to the epidermis and the dermis region, which contains many Langerhans and dendritic cells. The microneedle array looks like band-aid patches and offers the advantages of avoiding cold-chain storage and self-administration flexibility. The slow release of vaccine antigens is an important advantage of using microneedles. The vaccine antigens in the microneedles can be in solution or suspension form, encapsulated in nano or microparticles, and nucleic acid-based. The use of microneedles to deliver particle-based vaccines is gaining importance because of the combined advantages of particulate vaccine and pain-free immunization. The future of microneedle-based vaccines looks promising however, addressing some limitations such as dosing inadequacy, stability and sterility will lead to successful use of microneedles for vaccine delivery. This review illustrates the recent research in the field of microneedle-based vaccination.

The Possible Relationship between the Abuse of Tobacco, Opioid, or Alcohol with COVID-19.

Introduction: Substance use disorder has been frequently reported to increase the risk of infectious diseases, which might be owing to the sharing of contaminated inhalation, smoking, vaping, or injection equipment. Aim: This review analyzes the recent literature with the aim to put in light the possible relationship between the abuse of different substances (Tobacco, opioid, and Alcohol) with coronavirus disease (COVID-19). Tobacco: Multiple studies confirmed that cigarette smoking affects the respiratory system by increasing the expression of angiotensin-converting enzyme-2 (ACE2) receptors, which have a significant association with COVID-19 infection rate and disease severity. Opioid: Studies conducted regarding the association of opioid use disorder (OUD) and COVID-19 infection severity are limited; however, opioids can lead to both respiratory depression and kidney injuries, causing poor prognosis for those with COVID-19 infections. Alcohol: People with alcohol use disorders are at risk of developing acute lung injury and severe COVID-19 infection. Alcohol consumption during the COVID-19 pandemic has two possible scenarios: either increased or decreased based on situations. Conclusion: SUD has been frequently reported to have a positive relationship with COVID-19 severity Further studies are needed to understand the effects of opioids and alcohol abuse on COVID-19.

The Possible Relationship between the Abuse of Tobacco, Opioid, or Alcohol with COVID-19

Introduction: Substance use disorder has been frequently reported to increase the risk of infectious diseases, which might be owing to the sharing of contaminated inhalation, smoking, vaping, or injection equipment. Aim: This review analyzes the recent literature with the aim to put in light the possible relationship between the abuse of different substances (Tobacco, opioid, and Alcohol) with coronavirus disease (COVID-19). Tobacco: Multiple studies confirmed that cigarette smoking affects the respiratory system by increasing the expression of angiotensin-converting enzyme-2 (ACE2) receptors, which have a significant association with COVID-19 infection rate and disease severity. Opioid: Studies conducted regarding the association of opioid use disorder (OUD) and COVID-19 infection severity are limited;however, opioids can lead to both respiratory depression and kidney injuries, causing poor prognosis for those with COVID-19 infections. Alcohol: People with alcohol use disorders are at risk of developing acute lung injury and severe COVID-19 infection. Alcohol consumption during the COVID-19 pandemic has two possible scenarios: either increased or decreased based on situations. Conclusion: SUD has been frequently reported to have a positive relationship with COVID-19 severity Further studies are needed to understand the effects of opioids and alcohol abuse on COVID-19.