Recent advances of nanotechnology in COVID 19: A critical review and future perspective

The global anxiety and economic crisis causes the deadly pandemic coronavirus disease of 2019 (COVID 19) affect millions of people right now. Subsequently, this life threatened viral disease is caused due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, morbidity and mortality of infected patients are due to cytokines storm syndrome associated with lung injury and multiorgan failure caused by COVID 19. Thereafter, several methodological advances have been approved by WHO and US-FDA for the detection, diagnosis and control of this wide spreadable communicable disease but still facing multi-challenges to control. Herein, we majorly emphasize the current trends and future perspectives of nano-medicinal based approaches for the delivery of anti-COVID 19 therapeutic moieties. Interestingly, Nanoparticles (NPs) loaded with drug molecules or vaccines resemble morphological features of SARS-CoV-2 in their size (60–140 nm) and shape (circular or spherical) that particularly mimics the virus facilitating strong interaction between them. Indeed, the delivery of anti-COVID 19 cargos via a nanoparticle such as Lipidic nanoparticles, Polymeric nanoparticles, Metallic nanoparticles, and Multi-functionalized nanoparticles to overcome the drawbacks of conventional approaches, specifying the site-specific targeting with reduced drug loading and toxicities, exhibit their immense potential. Additionally, nano-technological based drug delivery with their peculiar characteristics of having low immunogenicity, tunable drug release, multidrug delivery, higher selectivity and specificity, higher efficacy and tolerability switch on the novel pathway for the prevention and treatment of COVID 19. © 2022 The Author(s)

Formulation, Device, and Clinical Factors Influencing the Targeted Delivery of COVID-19 Vaccines to the Lungs.

The COVID-19 pandemic has proven to be an unprecedented health crisis in the human history with more than 5 million deaths worldwide caused to the SARS-CoV-2 and its variants ( https://www.who.int/emergencies/diseases/novel-coronavirus-2019 ). The currently authorized lipid nanoparticle (LNP)-encapsulated mRNA vaccines have been shown to have more than 90% vaccine efficacy at preventing COVID-19 illness (Baden et al. New England J Med 384(5):403-416, 2021; Thomas et al., 2021). In addition to vaccines, other small molecules belonging to the class of anti-viral and anti-inflammatory compounds have also been prescribed to reduce the viral proliferation and the associated cytokine storm. These anti-viral and anti-inflammatory compounds have also been shown to be effective in reducing COVID-19 exacerbations especially in reducing the host inflammatory response to SARS-CoV-2. However, all of the currently FDA-authorized vaccines for COVID-19 are meant for intramuscular injection directly into the systemic circulation. Also, most of the small molecules investigated for their anti-COVID-19 efficacy have also been explored using the intravenous route with a few of them explored for the inhalation route (Ramakrishnan et al. Lancet Respir Med 9:763-772, 2021; Horby et al. N Engl J Med 384(8):693-704, 2021). The fact that the SARS-CoV-2 enters the human body mainly via the nasal and airway route resulting in the lungs being the primary organs of infection as characterized by acute respiratory distress syndrome (ARDS)-mediated cytokine storm in the alveolar region has made the inhalation route gain significant attention for the purposes of targeting both vaccines and small molecules to the lungs (Mitchell et al., J Aerosol Med Pulm Drug Deliv 33(4):235-8, 2020). While there have been many studies reporting the safety and efficacy of targeting various therapeutics to the lungs to treat COVID-19, there is still a need to match the choice of inhalation formulation and the delivery device platform itself with the patient-related factors like breathing pattern and respiratory rate as seen in a clinical setting. In that perspective, this review aims to describe the various formulation and patient-related clinical factors that can play an important role in the judicious choice of the inhalation delivery platforms or devices for the development of inhaled COVID-19 vaccines.

A Self-Emulsified Adjuvant System Containing the Immune Potentiator Alpha Tocopherol Induces Higher Neutralizing Antibody Responses than a Squalene-Only Emulsion When Evaluated with a Recombinant Cytomegalovirus (CMV) Pentamer Antigen in Mice.

The development of new vaccine adjuvants represents a key approach to improvingi the immune responses to recombinant vaccine antigens. Emulsion adjuvants, such as AS03 and MF59, in combination with influenza vaccines, have allowed antigen dose sparing, greater breadth of responses and fewer immunizations. It has been demonstrated previously that emulsion adjuvants can be prepared using a simple, low-shear process of self-emulsification (SE). The role of alpha tocopherol as an immune potentiator in emulsion adjuvants is clear from the success of AS03 in pandemic responses, both to influenza and COVID-19. Although it was a significant formulation challenge to include alpha tocopherol in an emulsion prepared by a low-shear process, the resultant self-emulsifying adjuvant system (SE-AS) showed a comparable effect to the established AS03 when used with a quadrivalent influenza vaccine (QIV). In this paper, we first optimized the SE-AS with alpha tocopherol to create SE-AS44, which allowed the emulsion to be sterile-filtered. Then, we compared the in vitro cell activation cytokine profile of SE-AS44 with the self-emulsifying adjuvant 160 (SEA160), a squalene-only adjuvant. In addition, we evaluated SE-AS44 and SEA160 competitively, in combination with a recombinant cytomegalovirus (CMV) pentamer antigen mouse.

Recent Updates in Vaccine Delivery through Microneedles.

Recent coronavirus pandemic and its global socio-economic impact has re-emphasized the need for safe, fast, and efficient delivery of vaccines for humankind. With advent of technological advances, and to improve patient acquiescence, several techniques for fast, effective, and safe delivery of vaccines have been researched and published in the literature in last three decades. These delivery enhancement techniques include but are not limited to electroporation, microneedles (MN), ultrasound, iontophoresis, etc. This review aims at discussing the current research undergoing in vaccine delivery, specifically focusing on microneedles assisted, the historical background of microneedles and their introduction to drug delivery area, and a special focus on formulation challenges and stability in these systems. The review also sheds light on regulatory challenges one must keep in mind for bringing a successful microneedles-based vaccine delivery into market as well as a snapshot of current commercially available microneedles-based products in cosmetic and pharmaceutical industry.

Enhancing neutralizing antibodies against receptor binding domain of SARS-CoV-2 by a safe natural adjuvant system.

The receptor binding domain (RBD) plays a pivotal role in the viral entry as it enables the engagement of severe acute respiratory syndrome 2 (SARS-CoV-2) with the human angiotensin-converting enzyme 2 (ACE2) receptor for host cell entry. RBD is the major target for developing viral inhibitors and vaccines. Expression of recombinant RBD in E.coli is highly scalable with a low-cost procedure despite its high expression level compared to expression in mammalian and yeast cells. Using an alternative natural adjuvant system instead of alum adjuvant, increased immunogenicity of RBD antigen in serological assay including direct ELISA and surrogate Virus Neutralization Test (sVNT) was demonstrated with high levels of IgGs and neutralizing antibodies in mice sera immunized with RBD:AlSa (Alum and Sodium alginate) formulation. The sVNT is a simple and fast test that can be used instead of the conventional virus neutralization test requiring live virus and BSL3 laboratory to detect total neutralizing antibodies against RBD. Additionally, results showed a safety profile for sodium alginate which supported using it as an alternative natural adjuvant.

Recent Advances of Nanotechnology in COVID 19: A critical review and future perspective

The global anxiety and economic crisis causes the deadly pandemic coronavirus disease of 2019 (COVID 19) affect millions of people right now. Subsequently, this life threatened viral disease is caused due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, morbidity and mortality of infected patients are due to cytokines storm syndrome associated with lung injury and multiorgan failure caused by COVID 19. Thereafter, several methodological advances have been approved by WHO and US-FDA for the detection, diagnosis and control of this wide spreadable communicable disease but still facing multi-challenges to control. Herein, we majorly emphasize the current trends and future perspectives of nano-medicinal based approaches for the delivery of anti-COVID 19 therapeutic moieties. Interestingly, Nanoparticles (NPs) loaded with drug molecules or vaccines resemble morphological features of SARS-CoV-2 in their size (60-140 nm) and shape (circular or spherical) that particularly mimics the virus facilitating strong interaction between them. Indeed, the delivery of anti-COVID 19 cargos via a nanoparticle such as Lipidic nanoparticles, Polymeric nanoparticles, Metallic nanoparticles, and Multi-functionalized nanoparticles to overcome the drawbacks of conventional approaches, specifying the site-specific targeting with reduced drug loading and toxicities, exhibit their immense potential. Additionally, nano-technological based drug delivery with their peculiar characteristics of having low immunogenicity, tunable drug release, multidrug delivery, higher selectivity and specificity, higher efficacy and tolerability switch on the novel pathway for the prevention and treatment of COVID 19.

Nanomaterial-based delivery of vaccine through nasal route: Opportunities, challenges, advantages, and limitations

Mucosal administration especially via the nasal route is a novel and promising technique for medication and vaccine delivery. Mucosal pathways provide notable benefits that promote their selective usage for some critical disorders such as brain disorders. Many attempts are now being undertaken to create effective medicated formulations and innovative nasal delivery methods. The structure and major properties of the nasal cavity are elaborated on in this review. The comfort, accomplishments, and limitations of using the nasal route for medical reasons are explored, with a special emphasis on vaccination administration. Extensive data supports the potential and safety of nasal vaccination and medication administration. The utilization of nanomaterials in vaccinology has changed several areas of traditional disease diagnosis and treatment and has brought new insights into previously tough challenges in developing effective vaccinations. This overview will focus on crucial advances of nanomaterial in vaccine delivery through the nasal route against infectious diseases. Copyright © 2022

In vivo fate and intracellular trafficking of vaccine delivery systems.

With the pandemic of severe acute respiratory syndrome coronavirus 2, vaccine delivery systems emerged as a core technology for global public health. Given that antigen processing takes place inside the cell, the intracellular delivery and trafficking of a vaccine antigen will contribute to vaccine efficiency. Investigations focusing on the in vivo behavior and intracellular transport of vaccines have improved our understanding of the mechanisms relevant to vaccine delivery systems and facilitated the design of novel potent vaccine platforms. In this review, we cover the intracellular trafficking and in vivo fate of vaccines administered via various routes and delivery systems. To improve immune responses, researchers have used various strategies to modulate vaccine platforms and intracellular trafficking. In addition to progress in vaccine trafficking studies, the challenges and future perspectives for designing next-generation vaccines are discussed.

Modeling anticipated changes in numbers of SARS-CoV-2 infections within communities due to immunization campaigns.

Background: As SARS-CoV-2 spread in early 2020, uncertainty about the scope, duration, and impact of the unfolding outbreaks caused numerous countries to interrupt many routine activities, including health services. Because immunization is an essential health service, modeling changes in SARS-CoV-2 infections among communities and health workers due to different vaccination activities was undertaken to understand the risks and to inform approaches to resume services. Methods: Agent-based modeling examined the impact of Supplemental Immunization Activities (SIAs) delivery strategies on SARS-CoV-2 transmission in communities and health workers for six countries capturing various demographic profiles and health system performance: Angola, Ecuador, Lao PDR, Nepal, Pakistan, and Ukraine. Results: Urban, fixed-post SIAs during periods of high SARS-CoV-2 prevalence increased infections within the community by around 28 [range:0-79] per 1000 vaccinations. House-to-house SIAs in mixed urban and rural contexts may import infections into previously naïve communities. Infections are elevated by around 60 [range:0-230] per 1000 vaccinations, but outcomes are sensitive to prevalence in health workers and SIA timing relative to peak. Conclusions: Younger populations experience lower transmission intensity and fewer excess infections per childhood vaccine delivered. Large rural populations have lower transmission intensity but face a greater risk of introduction of SARS-CoV-2 during an SIA.

Cutting-Edge Delivery Systems and Adjuvants in Tolerogenic Vaccines: A Review.

Conventional therapies for immune-mediated diseases, including autoimmune disorders, transplant reactions, and allergies, have undergone a radical evolution in the last few decades; however, they are still not specific enough to avoid widespread immunosuppression. The idea that vaccine usage could be extended beyond its traditional immunogenic function by encompassing the ability of vaccines to induce antigen-specific tolerance may revolutionize preventive and therapeutic strategies in several clinical fields that deal with immune-mediated disorders. This approach has been supported by improved data relating to the several mechanisms involved in controlling unwanted immune responses and allowing peripheral tolerance. Given these premises, several approaches have been developed to induce peripheral tolerance against the antigens that are involved in the pathological immune response, including allergens, autoantigens, and alloantigens. Technological innovations, such as nucleic acid manipulation and the advent of micro- and nanoparticles, have further supported these novel preventive and therapeutic approaches. This review focuses on the main strategies used in the development of tolerogenic vaccines, including the technological issues used in their design and the role of "inverse adjuvants". Even though most studies are still limited to the preclinical field, the enthusiasm generated by their results has prompted some initial clinical trials, and they show great promise for the future management of immune-mediated pathological conditions.

The Race to Develop the Pfizer-BioNTech COVID-19 Vaccine: From the Pharmaceutical Scientists' Perspective.

At the outset of the coronavirus disease 2019 (COVID-19) pandemic, it was clear that a vaccine would be crucial for global health efforts. The Pfizer and BioNTech teams came together in a race against the virus, working to design, test, manufacture, and distribute a safe and efficacious vaccine in record time for people around the world. Here, we provide backstory commentary from the pharmaceutical scientist perspective on the challenges and solutions encountered in the development of the Pfizer-BioNTech mRNA COVID-19 vaccine (BNT162b2; b2; Comirnaty®; tozinameran). We discuss the foundational science that led to the decision to use an mRNA-based approach. We also describe key challenges in the identification of an optimal vaccine candidate and testing in clinical trials, the continuous efforts to improve the vaccine formulation in response to changing global health priorities and facilitate vaccine accessibility, and how vast quantities of vaccine doses were manufactured and safely delivered to every corner of the globe, all without compromising quality, science, and safety. The key to successfully delivering a safe and efficacious vaccine within nine months was a result of extraordinary, real-time, parallel effort and across-the-board collaboration between stakeholders on a global scale.

The Uncertain Times of COVID Mass Vaccine Deliveries: from Start-up to Steady-State

Mass vaccination campaigns have been adopted throughout the world as a major tool to stop the spread of COVID or at least abate its lethal consequences. Smart vaccination strategies have been proposed to make the most efficient use of the scarce resources (e.g., medical and nursing staff) and achieve vaccination aims (i.e., vaccinating as many people as possible in the shortest possible time). However, smart strategies may fail if vaccine deliveries are erratic or do not exhibit even statistical regularity. In this paper, we perform a statistical analysis of up-to-date vaccine delivery data to uncover regularities and use them to draw a probabilistic model of vaccine deliveries that may help optimize and evaluate smart vaccination strategies. We find that for two out of three vaccine manufacturing companies, deliveries concentrate on one or at most two days over a week, though the actual day may be modelled by an arithmetic distribution. © 2022 IEEE.

Challenges and opportunities in current vaccine technology and administration: A comprehensive survey examining oral vaccine potential in the United States.

This study provides a snapshot of the current vaccine business ecosystem, including practices, challenges, beliefs, and expectations of vaccine providers. Our team focused on providers' firsthand experience with administering vaccines to determine if an oral vaccine (e.g. pill or oral-drop) would be well-received. We interviewed 135 healthcare providers and vaccine specialists across the US, focusing questions on routine vaccinations, not COVID-19 vaccines. Improving workflow efficiency is a top concern among vaccine providers due to shrinking reimbursement rates-determined by pharmacy benefit managers (PBMs)-and the time-intensiveness of injectable vaccines. Administering injectable vaccines takes 23 minutes/patient on average, while dispensing pills takes only 5 minutes/patient. An average of 24% of patients express needle-fear, which further lengthens the processing time. Misaligned incentives between providers and PBMs could reduce the quality and availability of vaccine-related care. The unavailability of single-dose orders prevents some rural providers from offering certain vaccines. Most interviewees (74%) believe an oral vaccine would improve patient-provider experience, patient-compliance, and workflow efficiency, while detractors (26%) worry about the taste, vaccine absorption, and efficacy. Additional research could investigate whether currently non-vaccinating pharmacies would be willing to offer oral vaccines, and the impact of oral vaccines on vaccine acceptance.

Delivery of MERS antigen encapsulated in α-GalCer-bearing liposomes elicits stronger antigen-specific immune responses.

Alpha-Galactosylceramide (α-GalCer) effectively activates the natural killer T (NKT) cells to secrete remarkable amounts of Th1 and Th2 cytokines and therefore, acts as a potential immunoadjuvant in vaccine formulation. In the present study, we prepared α-GalCer-bearing or α-GalCer-free liposomes and loaded them with Middle East Respiratory Syndrome Coronavirus papain-like protease (α-GalCer-Lip-MERS-CoV PLpro or Lip-MERS-CoV PLpro). These formulations were injected in mice to investigate the antigen-specific humoral and cell-mediated immune responses. The immunisation with α-GalCer-Lip-MERS-CoV PLpro or Lip-MERS-CoV PLpro did not induce any notable toxicity in immunised mice. The results demonstrated that mice immunised with α-GalCer-Lip-MERS-CoV PLpro showed greater antigen-specific antibody titre, switching of IgG isotyping to IgG2a subclass and higher lymphocyte proliferation. Moreover, the splenocytes from α-GalCer-Lip-MERS-CoV PLpro immunised mice secreted greater levels of IFN-γ, IL-4, IL-2 and IL-12. Interestingly, a booster dose induced stronger memory immune responses in mice previously immunised with α-GalCer-Lip-MERS-CoV PLpro. In summary, α-GalCer-Lip-MERS-CoV PLpro may prove to be a promising vaccine formulation to protect the individuals against MERS-CoV infection.

Immune response induced in rodents by anti-CoVid19 plasmid DNA vaccine via pyro-drive jet injector inoculation.

There is an urgent need to stop the coronavirus disease 2019 (COVID-19) pandemic through the development of efficient and safe vaccination methods. Over the short term, plasmid DNA vaccines can be developed as they are molecularly stable, thus facilitating easy transport and storage. pVAX1-SARS-CoV2-co was designed for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) S protein. The antibodies produced led to immunoreactions against the S protein, an anti-receptor-binding-domain, and a neutralizing action of the pVAX1-SARS-CoV2-co, as previously confirmed. To promote the efficacy of the pVAX1-SARS-CoV2-co vaccine a pyro-drive jet injector (PJI) was used. An intradermally adjusted PJI demonstrated that the pVAX1-SARS-CoV2-co vaccine injection caused a high production of anti-S protein antibodies, triggered immunoreactions, and neutralized the actions against SARS-CoV-2. A high-dose pVAX1-SARS-CoV2-co intradermal injection using PJI did not cause any serious disorders in the rat model. A viral challenge confirmed that intradermally immunized mice were potently protected from COVID-19. A pVAX1-SARS-CoV2-co intradermal injection using PJI is a safe and promising vaccination method for overcoming the COVID-19 pandemic.

Opportunities and challenges for commercializing microarray patches for vaccination from a MAP developer's perspective.

Continued advances in microarray patch (MAP) technology are starting to make needle-free delivery of a broad range of vaccines an achievable goal. The drivers and potential benefits of a MAP platform for pandemic response and routine vaccination are clear and include dose-sparing, cold-chain elimination, increased safety, and potential self-administration. MAP technology is regarded as a priority innovation to overcome vaccination barriers, ensure equitable access, and improve the effectiveness of vaccines. Vaxxas, a global leader in this technology, has built a strong evidence-base for the commercial application of their high-density (HD) MAP platform, and is rapidly advancing scale-up of the manufacturing process for HD-MAPs. A greater awareness and understanding of the implications of the technology amongst supply-chain participants, regulatory authorities, and global healthcare organizations and foundations is needed to accelerate adoption and, particularly, to prepare for MAP use in pandemics. Key challenges remain in the commercialization of MAP technology and its adoption, including market acceptance, scale-up of production, regulatory approval, and the availability of capital to build advanced manufacturing infrastructure ahead of late-stage clinical trials.

Mucosal vaccine delivery: A focus on the breakthrough of specific barriers.

Mucosal vaccines can effectively induce an immune response at the mucosal site and form the first line of defense against microbial invasion. The induced mucosal immunity includes the proliferation of effector T cells and the production of IgG and IgA antibodies, thereby effectively blocking microbial infection and transmission. However, after a long period of development, the transformation of mucosal vaccines into clinical use is still relatively slow. To date, fewer than ten mucosal vaccines have been approved. Only seven mucosal vaccines against coronavirus disease 2019 (COVID-19) are under investigation in clinical trials. A representative vaccine is the adenovirus type-5 vectored COVID-19 vaccine (Ad5-nCoV) developed by Chen and coworkers, which is currently in phase III clinical trials. The reason for the limited progress of mucosal vaccines may be the complicated mucosal barriers. Therefore, this review summarizes the characteristics of mucosal barriers and highlights strategies to overcome these barriers for effective mucosal vaccine delivery.

mRNA as a Therapeutics: Understanding mRNA Vaccines.

Vaccination is one of the important approaches in the prevention and control of diseases. Although the capacity to present antigens other than the disease-specific antigen in the traditional vaccine composition provides a potential benefit by increasing its protective efficacy, many components that are not needed for the related disease are also transferred. These components can reduce vaccine activity by lowering immunity against protective antigens. The reasons such as the low effectiveness of traditional vaccines and the high cost of production and time-consuming reasons show that it is necessary to develop a new vaccine method for our world, which is struggling with epidemics almost every year. Among nucleic acids, mRNA has many advantages, such as genomic integration, induction of anti-DNA autoantibodies, and immune tolerance induced by long-term antigen expression. mRNA vaccines have become a therapeutic target for reasons such as efficacy, safety, fast and non-expensive production. The fact that mRNA triggers both humoral and cellular immunity and goes only to the cytoplasm, not to the nucleus, makes it highly efficient. The mRNA must cross the lipid bilayer barrier and entry to the cytoplasm where it is translated into protein. There are two main ways of mRNA vaccine delivery for this: ex vivo loading of mRNA into dendritic cells (DCs) and direct injection of mRNA with or without a carrier. Studies continue to understand which delivery system is therapeutically more efficient. Preclinical and clinical trials showed that mRNA vaccines trigger a long-lasting and safe immune response.

The Current Landscape of mRNA Vaccines Against Viruses and Cancer-A Mini Review.

Both infectious viral diseases and cancer have historically been some of the most common causes of death worldwide. The COVID-19 pandemic is a decidedly relevant example of the former. Despite progress having been made over past decades, new and improved techniques are still needed to address the limitations faced by current treatment standards, with mRNA-based therapy emerging as a promising solution. Highly flexible, scalable and cost-effective, mRNA therapy is proving to be a compelling vaccine platform against viruses. Likewise, mRNA vaccines show similar promise against cancer as a platform capable of encoding multiple antigens for a diverse array of cancers, including those that are patient specific as a novel form of personalized medicine. In this review, the molecular mechanisms, biotechnological aspects, and clinical developments of mRNA vaccines against viral infections and cancer are discussed to provide an informative update on the current state of mRNA therapy research.

Potential of Microneedle Systems for COVID-19 Vaccination: Current Trends and Challenges.

To prevent the coronavirus disease 2019 (COVID-19) pandemic and aid restoration to prepandemic normality, global mass vaccination is urgently needed. Inducing herd immunity through mass vaccination has proven to be a highly effective strategy for preventing the spread of many infectious diseases, which protects the most vulnerable population groups that are unable to develop immunity, such as people with immunodeficiencies or weakened immune systems due to underlying medical or debilitating conditions. In achieving global outreach, the maintenance of the vaccine potency, transportation, and needle waste generation become major issues. Moreover, needle phobia and vaccine hesitancy act as hurdles to successful mass vaccination. The use of dissolvable microneedles for COVID-19 vaccination could act as a major paradigm shift in attaining the desired goal to vaccinate billions in the shortest time possible. In addressing these points, we discuss the potential of the use of dissolvable microneedles for COVID-19 vaccination based on the current literature.