Coronavirus-19 disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The long incubation era of this new virus, which is generally asymptomatic but contagious, is one of the main reasons for its immediate spread worldwide. Currently, there is no approved international remedy for COVID-19. As a result, clinical and clinical communities are running in combination to lessen the serious consequences of the epidemic. Research into emerging infectious diseases in the past has created valuable wisdom that is being harnessed for drug reuse and accelerated vaccine development. However, it is vital to generate wisdom about the mechanisms of SARS-CoV-2 infection and its effect on host immunity, to consult the design of specific COVID-19 treatments and vaccines suitable for mass vaccination. Nanoscale supply systems are expected to play a key role in the good fortune of these prophylactic and curative approaches. This review provides a review of sarS-CoV-2 pathogenesis and examines the immunomediated approaches that are being recently explored for COVID-19 remedies, with an emphasis on nanotechnology tools.
The coronavirus-19 disease pandemic (COVID-19), caused by severe acute respiratory syndrome (SARS-CoV-2) coronavirus 2, was first reported in Wuhan, China, in December 2019. Since then, it has spread around the world, already infecting millions of people around the world. As of 30 June 2020, 213 countries had reported cases of COVID-19, with a total number of more than 10.3 million, the highest in the United States (2.6 million), Brazil (1.4 million), Russia (640 thousand), India (548 thousand) and the United Kingdom (314 thousand). The United States has the highest number of deaths (126,000), followed by Brazil (58,000), the United Kingdom (44,000) and Italy (35,000). The overall case rate in all communities is 4.9%.
Coronaviruses (CoVs) are wrapped viruses that trap un segmented, positive, and single-stranded ribonucleic acid (RNVs). The length of its genome levels is 26 to 32 kb, being the largest known RNA virus. The end of the SARS-CoV-3′ code for structural proteins, adding complex glucoproteins (S) 1.2, membrane glucoproteins (M) 3, as well as wrapping proteins (E) four and nucleocapside (N) 2.5 (Fig. .1). In addition to genes encoding structural proteins, there are express genomic regions that encode viral proteins for replication6, in addition to other non-structural proteins, such as papain protease (PLpro) 7 and the main coronavirus protease (3CLpro) 8
Schematic representation of SARS-CoV-2 design. It is a positive-sense wrapped RNA virus with 4 major structural proteins, which adds complex glucoproteins (S) and membranes (M), such as wrapping proteins (E) and nucleopsid (N).
According to the Center for Disease Control and Prevention (CDC), the incubation period following infection is 2–14 days, with an estimated median of 5.1 days9,10. However, cases with longer incubation of 24 days have been reported11. The long incubation period is the primary reason for the massive infection, as it is mostly asymptomatic yet contagious10. Although the estimated patients’ age average is ~70, all age groups are susceptible to this virus. However, the elder population (>60) and people with comorbidities are more likely to develop severe symptoms upon infection12.
Much like previous CoVs, severe acute respiratory syndrome (SARS) and Middle East respiratory ryndrome (MERS), SARS-CoV-2 is predominantly infecting the lower airways, ranging from mild respiratory illness to severe acute respiratory syndrome and septic shock in advanced stages6. The most commonly reported symptoms are fever, dry cough, dyspnea, fatigue and myalgia, which are early characteristics of the most frequent manifestation of SARS-CoV-2 infection, pneumonia13,14,15. Physicians and pathologists are also reporting devastating damage to the cardiovascular system, gut, kidneys and brain16,17. Of importance is the recently observed tendency of COVID-19 patients´ blood to clot, which leads to vessel constriction and ultimately can result in pulmonary embolism or large-vessel ischemic stroke, in addition to ischemia in fingers and toes16,18.
On 7 May, remdesivir was approved for COVID-19 in Japan19. In the rest of the world, there are no specific treatments or vaccines available for COVID-19. To the best of our knowledge, the only available options are the condition marketing authorization to remdesivir recommended by the European Medicines Agency (EMA) on 25 June, as well as the emergency use authorizations (EUA) provided by the US Food and Drug Administration (FDA) on 1 May for remdesivir20, on 30 March for the decades-old malaria drugs hydroxychloroquine sulfate and chloroquine phosphate21, and on 24 March for the infusion of plasma of COVID-19 convalescent patients22. The latter was supported by data obtained on only 5 critically ill COVID-19 patients23, which had high levels of neutralizing antibodies, raising the realistic hope of producing virus-specific enriched immunoglobulins, similarly to the ones used for tetanus, hepatitis A/B, cytomegalovirus, varicella and measles. On 2 June, a clinical trial designed to evaluate the safety and tolerability of the antibody LY-CoV555 was posted. This IgG1 antibody is the first potential preventive and therapeutic medicine developed to specifically target the spike protein on the SARS-CoV-224.
Immediate spread of SARS-CoV-2 requires accelerated progression times for COVID-19 vaccines and cure applicants to temporarily enter Phase 1 clinical trials. Therefore, the type and scope of preclinical and initial clinical knowledge needed to determine these clinical progression systems will need to be weighed as opposed to the overall assessment of the dangers and benefits of this unmet medical need. In fact, to date, the maximum published clinical trials on prophylactic and curative methods opposed to COVID-19 have countless weaknesses, such as not being randomized or controlled, reading small populations and/or losing a placebo group, making it difficult to achieve conclusive results.
As of 30 June, 2,351 clinical trials are listed in ClinicalTrials.gov, using COVID-19, 2019-nCOV, SARS-CoV-2 or 2019 novel coronavirus as search terms (Fig. 2). Most of trial locations are reported in Europe (709), North America (441), Asia (200) and the Middle East (94).
Summary of COVID-19 trials first posted on ClinicalTrials.gov per month (30 June 2020). The search terms COVID-19, 2019-nCOV, SARS-CoV-2 or 2019 novel coronavirus resulted in 2,351 trials, including 185 with hydroxycholoroquine/chloroquine, 25 with remdesivir, 375 with other repurposed drugs, 48 with vaccines, 217 with immune-modulatory approaches, 118 with convalescent plasma, 202 with diagnostic tests and 41 with dietary supplements.
The strong commitment of the scientific community in addressing COVID-19 disease and global social and economic impact led already to the publication of 27,255 manuscripts (as of 30 June, using keywords COVID-19 or SARS-CoV-2) and submission of 5,891 preprints (4,701 medRxiv, 1,190 bioRxiv). Thus, the large amount of information generated and reported in the last months raises the need for a consensus analysis.
The similarities found between SARS-CoV-2 and SARS-CoV, MERS-CoV, or human immunodeficiency viruses (HIV) can enhance the development of potential therapeutic approaches and advance the understanding of the virus mechanism of action25,26,27,28. Currently, major efforts are being invested around the world by commercial vaccine manufacturers, pharmaceutical companies, biotech entities and laboratories at academic institutions to accelerate the discovery and development of prophylactic and therapeutic solutions against SARS-CoV-2 infection using technologies and platforms mostly based on therapeutic modalities developed against these previous infectious diseases. These include repurposing of antivirals (for example, viral polymerase and protease inhibitors29,30), anti-inflammatory drugs31,32, monoclonal antibodies (mAb)27, antibiotics and immune modulators (for example, anti-interleukin-6 (IL-6) agents33,34, PEGylated interferon (IFN)-alpha and beta (PEG-IFN-α/β)35,36), activators of toll-like receptors (TLR)37 and vaccines (for example, based on whole virus38, messenger RNA (mRNA)39, DNA40,41, recombinant proteins42 and peptides43, including when packaged in diverse delivery systems, as well as viral-vectored vaccines44,45 and virus-like particles (VLP)46).
Hydroxychloroquine sulfate and chloroquine phosphate are antimalarial drugs that have been shown to adjust the acidic situations of organelles in mobile culture studies of mammals47, as well as inhibit the terminal glycosylation of ACE2 in vitro as opposed to SARS-CoV48, indicating their role in preventing the fusion of the virus with the mobile membrane and , therefore, blocks SARS-CoV-2 infection. Hydroxychloroquine sulfate has been shown to have effects on immune mobile activation and the phenotype opposite lupus erythematosus49, indicating that it has an imaginable effect on the modulation of the host’s immune reaction during SARS-CoV-250,51,52 infection. Hydroxychloroquine sulfate is also tested in mixture with a variety of medicines, adding the antibiotic azithromycin, to treat patients with COVID-1953.
Viruses commonly use express enzymes that act on mechanisms other than human mobile biology, so they can be used as express targets for the remedy of viral infections. In vitro studies have shown that umifenovin inhibits SARS access to mobile phones through discontinuation of the enzymatic interaction of angiotensin protein 2 (ACE2) / S, additional inhibition of viral envelope fusion54, which is also effective in vivo against H1N155 viruses and A56 influenza. Umifenovir is lately considered as a COVID-19 remedy in mixture with protease inhibitors14,57.
Lopinavir and ritonavir (LPV/RTV) are protease inhibitors used to treat HIV infections by inhibiting HIV protease activity, which is essential for the maturation of the virus. Both are effective as opposed to MERS-CoV in mice58. Cobicistat is a cytochrome P450 (CYP) 3A inhibitor used as a pharmacokinetic amplifier in mixture with ritonavir for the treatment of HIV29,30. Other protease inhibitors, such as ASC09 and darunavir59, are being studied. Ribavirin is a broad-spectrum antiviral drug recently used as a popular remedy for hepatitis C virus, in mixture with PEG-IFN-60. It is a ribonucleic analog that prevents replication of viral RNA61.
One of the most investigated drugs at the moment is remdesivir, an adenosine nucleotide analogue that interferes with the viral RNA-polymerase activity, recently approved for COVID-19 treatment in Japan. Remdesivir was shown to be effective against the SARS-CoV virus in vitro and is under evaluation in clinical trials62. Preliminary data on a randomized, placebo-controlled trial of remdesivir enrolling 1063 patients have been released on 22 May, showing that the drug was overall safe and effective for COVID-19 patients, leading to a shorter time to recovery than that obtained in the placebo group63. Similarly, favipiravir is a guanine analogue that also acts as an RNA polymerase inhibitor, currently used for influenza treatment, and 38 clinical trials were recently initiated to assess its effect against COVID-1964,65. Other antivirals currently being considered in COVID-19 clinical trials include the neuraminidase inhibitor oseltamivir and the viral endonuclease inhibitor baloxavir marboxil, both used against influenza infection66. In addition, azvudine is a reverse transcriptase inhibitor developed for HIV treatment that may also interfere with the viral replication67.
Additional clinical trials are exploring the use of anti-inflammatory agents to prevent patients with COVID-19 from having severe lung inflammation. These come with corticosteroids and nonsteroidal immunosuppressive agents, such as indomethacin and barcitinib68, in addition to mAb aimed at inflammatory cytokines, such as IL-6 and protein supplement five (Cfive). On June 16, the RECOVERY review announced the first effects of this randomized controlled clinical trial, which showed that the drug dexamethasone reduced the death of patients ventilated with COVID-19 by one third, supporting its prospective use as popular care in these patients69. Training
It is interesting to note that angiotensin receptor inhibitors (ARBs) and angiotensin conversion enzyme (ACE) inhibitors accumulate ace2 expression, prospectively expanding mobile infection with SARS-CoV-2. However, a population-based giant examination of 6272 COVID-19 patients found no correlation between the use of ACE or ARB inhibitors and SARS-CoV-270 infection. Therefore, in addition to the limited knowledge available, lately there is no clear evidence of discontinuation of these drugs, given the possible threat that this action may pose only in patients with a history of hypertension, central failure, post-heart attack and kidney disease.
Cell infection by pathogenic agents may trigger host humoral and cellular immunities essential to eliminate the viral infection. However, an uncontrolled or insufficient immune response may lead to immunopathology and cause severe damage to patients71. A deeper understanding of the immune response induced by SARS-CoV-2 infection may lead to new immunotherapies while reducing the potential risk of inflammation.
The maximum known mechanism of mobile infection of SARS-CoV-2 is mediated through the ACE2 mobile surface receiver (Figure 3), similar to SARS-CoV65,72. Several studies have shown that SARS-CoV-2 is capable of infecting genetically modified mobiles to explain only the ACE230.73 receptor. Because this ACE2 receptor is primarily discovered in the human epithelium of the lung and small intestine, SARS-CoV-2 is more likely to infect the airways and gastrointestinal 72,74. The preprint published through Hikmet et al. indicates that ace2 ejection was also discovered in glandular mobiles of the seminal gallbladder, proximal renal tubules, cardiomyocytes, Sertoli testicular mobiles, Leydig mobiles and gallbladder epithelium75. In addition, it has been reported that the brain may also be inflamed with this virus, as patients with COVID-19 show neurological signs, such as hyposmia in the early stages of infection, but also nausea, vomiting, headaches and brain damage14 in severe cases. SITUATIONs SARS-CoV has been discovered in the brains of animals and patients76. SARS-CoV-2 has been reported to enter the brain through brain circulation, due to the presence of the ACE2 receptor in the endothelium, or sifted plaque near the olfactory bulb, possibly justifying at least partially the brain’s alteration. sense of smell. In fact, glial mobiles and neurons are known to exploit ACE277, thus being prospective targets for SARS-CoV-2.
a d, SARS-CoV-2 is internalized through the mobile through (i) membrane fusion or (ii) endocytosis. The peak of SARS-CoV-2 binds to the angiotensin 2 conversion enzyme (ACE2) its receptor binding domain (RBD) and also releases its RNA (b), which will result in viral proteins (c, d). e-h, these proteins will shape a replication complex to create more RNA (e) that will better bind with viral proteins in a new virus (f), which will be released (g, h). Seine transmembrnaire Protease 2 (TMPRSS2) is a protease that affects virus access, even if its deactivation does not inhibit mobile infection with SARS-CoV-2. TMPRSS2, seine transmembrnaire protease 2; ACE2, angiotensin conversion enzyme 2.
L-SIGN (CD209L) is a less explored potential SARS-CoV-2 receptor. It is a type II transmembrane glycoprotein of the C-type lectin family, mainly expressed in human lung alveolar epithelial type II cells and endothelial cells. This receptor was shown to mediate SARS-CoV entry into host cells, but at a lesser extent than the ACE2 receptor78,79. Therefore, CD209L is likely to mediate SARS-CoV-2 entry as well.
Surface-exposed glucoprotein S is the first viral component to interact with host mobiles, codifying through the S gene, the maximum variable region of the SARS-CoV30 genome. Protein S is a primary component to blame for viral binding, fusion and additional access to target mobiles. Includes two main functional units. The subunit SARS-CoV-2 S1, the recipient binding dressmajor (RBD), whose affinity for the binding to the host receptor varies according to the other CoVs, which affects the infection and dictates the severity of the disease6,80. The SARS-CoV-2 S2 subunit refers to the fusion of the virus with the mobile host membrane6.
The binding and/or entering mechanisms suggested for SARS-CoV-2 include several steps similar to those identified for SARS-CoV and MERS-CoV infection due to the RBD genomic similarity26. The virus entry is a complex process that starts with the recognition of the RBD 394 glutamine residue by the lysine 31 residue on the human ACE2, further adopting specific conformations that will allow a fast dissociation of the S1 and S2 subunits80,81 (Fig. 3). This proteolytic priming of the S protein by host proteases is also crucial to release the fusion peptide, enabling the viral and host cell membrane fusion, and subsequent release of SARS-CoV-2 RNA into the cytoplasm28,82,83.
Inhibition or purification of host proteases has been shown to block access to the virus in vitro, while the target mobile-related virus protease remedy has the opposite effect82,84,85,86. Seine transmembrnaire protease 2 (TMPRSS2) expressed in human lung mobiles is one of those proteases. The elimination of TMPRSS2 decreased viral access to mobile crops86, but was not enough to save SARS-CoV-2 infection. Further examination showed that complete inhibition of viral access was achieved when camostate mesilate, a clinically approved seine protease inhibitor, was related to catepsin B/L inhibitors. Previous studies on SARS-CoV infection have used other proteases, such as catepsine L and B, for mobile access87. This examination showed that inhibition of SARS-CoV membrane fusion activated by catepsin-sensitive endosmaloma pH in vitro membrane fusion, indicating that proteolysis of this catesine in endosomas would possibly be mandatory for fusion and viral access. Therefore, combinations of host mobile protease inhibitors are prospective treatments opposed to COVID-19, which conform to an active domain of studies.
Upon virus entry into host cells, genome RNA serves as mRNA for the first open reading frame (ORF1), being thus translated into viral replicase polyproteins that are later cleaved into small products by viral proteinases. These assemble on double-membrane vesicles that become sites for RNA viral synthesis, which has two stages. The first one constitutes the genome replication, while the second one includes the subgenomic RNA transcription and further translation into structural and accessory proteins from additional ORF78,88. These structural proteins are crucial for RNA synthesis by RNA-dependent RNA polymerases (RdRP) in order to replicate the genomic RNA that will be subsequently released upon fusion with plasma membrane89. The double-membranes enable the viral evasion of host immune responses by lacking the pattern recognition receptors (PRR), the activation of which is crucial for triggering host innate immunity against these viral invading pathogens90.
The first line of defence mounted by the host at the entry site, encompassing the induced expression of type I IFN (IFN-I) and other pro-inflammatory cytokines, was reported to be suppressed by SARS-CoV and MERS-CoV36, being related to disease severity.
The modulation of host IFN-I response involves the interference with the ubiquitination and degradation of RNA sensor molecules and the nuclear translocation of the IFN regulatory factor 3 (IRF3), as well as with the reduction of the signal transducer and activator of transcription 1 (SATA1) phosphorylation91,92. It has been already reported that high levels of the cytokine IL-6 were correlated with SARS-CoV-2 viral load in the blood of critically ill COVID-19 patients80.
In addition, the inhibition of cellular components of host immunity has also been reported for SARS-CoV-2 and MERS-CoV infections. The latter led to the downregulation of gene expression related to antigen presentation93, while increased levels of exhausted CD8+ T cells and loss of CD4+ T cell function were found in the peripheral blood of patients infected with SARS-CoV-294.
Therefore, the induction of a balanced host immune response against pathogens in general, and SARS-CoV-2 in particular, is crucial to control and eliminate infection, employing adaptive and innate immune responses, as well as events mediated by the complement system (Supplementary Table 1). On the one hand, an uncontrolled immunity may result in pulmonary tissue damage, functional impairment and reduced lung capacity71. On the other hand, immune insufficiency or misdirection may increase viral replication and cause tissue damage90.
Considering the infection rate of SARS-CoV-2, the prolonged incubation time and the associated high fatality rates, especially in those vulnerable high-risk populations, currently the only possible option to control COVID-19 pandemic is by quarantine, physical distancing and face masks. These measures have been adopted worldwide, but it is becoming an immense economic burden. Historically, vaccines were shown to be effective tools to abolish pandemics, and protect the population, especially high-risk groups, against a variety of viral infections95. Individuals that recover from SARS-CoV-2 infection may develop a protective immunity, considering the immune response triggered by other CoVs and recent findings reported in a small study performed in rhesus macaques, posted as a preprint to bioRxiv96. Even though it is currently unknown if humans previously exposed to the virus are protected against SARS-CoV-2, and there is no sufficient information on the impact of this infection on host immunity, the kinetics of the immune response detected in a patient with mild-to-moderate COVID-19 was recently reported97. The blood of this patient contained increased levels of activated CD4+ and CD8+ T cells, follicular T-helper cells, antibody-secreting cells and IgM/IgG SARS CoV-2-binding antibodies. However, it is not known if those titres are high enough and will remain for a period required to confer protection against re-infection. The antibody response against SARS-CoV was detected at 10–20 days98 and lasts for 2–3 years80.
More importantly, the clinical condition of five patients inflamed with SARS-CoV-2 who already have Acute Respiratory Difficulty Syndrome (SED), the maximum severe acute lung injury, took a step forward following plasma treatment containing neutralizing antibodies taken from patients cured of this disease. disease99Array Caution deserves to be exercised by drawing conclusions from a clinical examination involving such a small number of individuals, however, those observations show the enthusiasm related to the progression of COVID-19 vaccines.
Comparing a series of SARS-CoV-2 consensus proteins with the SARS-CoV, Bat-SARS-CoV and MERS-CoV series revealed a high degree of similarity between SARS-CoV and the SARS-like CoV bat. This contrasts with the small similarity to the MERS-CoV (additional table 2) 30,63,100.
Overall, limited data on SARS-CoV-2 and the similarity between the two viruses (SARS-CoV and SARS-CoV-2) led to the rational progression of SARS-CoV-2 vaccines based on the wisdom already available on betronaacovirus comparisons.
Among SARS-CoV-2 proteins, several studies recommend that structural proteins S and N be the promising maximum targets for vaccine design1,2,26,63,80,101. Because protein S has to do with the virus’s access to host cells, it is the primary goal of neutralizing antibody infection1,2. Protein N is a highly immunogenic protein that is widely expressed as SARS-CoV1,2 infection. In addition, it has been reported that the opposite T-cell responses to SARS-CoV-2 S, M and N proteins are among the dominant and long-lasting maximums100.
Several sequences of SARS-CoV epitopes were explained and compared to the SARS-CoV-2 sequence, the maximum of which was derived from the S and N proteins. In addition to characterizing the genomic sequences of SARS-CoV-2, the vaccine design requires the evaluation of its inherent antigenicity to identify candidate T-mobile and mobile epitopes B (Fig. 4). To this end, it is to perceive whether these sequences bind to the molecules of the Class I or Class II Histocompatibility Complex (CMH), and further verify their popularity and induction of the anti-SARS-CoV-2 immune reaction after activation of human and mobile B T-mobile mobiles.
Bioinformatics-assisted prediction of applicants for the epitope of T cells and B cells of SARS-CoV-2 given the similarity of the genomic design of SARS-CoV and SARS-CoV-2. Potential sequences of antigen epitopes are represented for protein N (PBD: 6VYO) and protein S (PBD: 6VXX). Potential antigen epitope sequences do not present for membrane (M) and wrapping (E) proteins, as crystallographic designs of these proteins are not yet available in Protein Data Bank.
Around the world, many study teams have analyzed several B and T mobile epitopes, mainly using bioinformatics equipment (Database and Virus Pathogen Analysis (ViPR) or The Immune Epitopes Database (IEDB). Although this is a research topic, the first Genome sequences became available on January 11, 2026100 and are a valuable source for the progression of CANDIDATEs for the COVID-19 vaccine.
The large amount of data generated and reported in recent months suggests the need for consensual analysis. We summarize the maximum described mobile epitopes of B and T that could possibly cause a cross-reaction and effective against SARS-CoV-2 (Additional table 3).
The pressing progression of a COVID-19 vaccine has led industries and researchers around the world to take advantage of vaccine platforms developed beyond other viral infections, such as SARS-CoV and MERS-CoV. Different approaches have been designed to stimulate and/or reprogram host immunity against viral diseases, in order to primarily induce Th1 immune responses and the production of binding antibodies and also neutralization against targeted proteins. The knowledge generated as a result of the clinical progression of these platforms is very important in identifying the most productive COVID-19 vaccine applicants by providing evidence of protection collected beyond biodistribution and toxicity studies.
Most candidate vaccines102 developed to fight SARS-CoV and MERS-CoV infections are based on the total virus (live attenuated or inactivated), as well as total viral subunits or proteins, DNA and RNA, including the use of -replication or replication of viral vectors, LPV or artificial delivery systems (Fig. 5). Conventional inactivated or live attenuated vaccines pose protective considerations due to the imaginable induction of the disease, as well as triggering a strong protective immune response, adding the observed against SARS-CoV103 infection. The effectiveness of viral vectors would possibly be compromised through potentially existing preimmunity, such as adenovirus. As a result, candidate vaccines, for example, based on low seroprevalence chimpanzee adenovirus in the human population104 have been explored in opposition to MERS, although their protection profile has not yet been fully treated in humans.
Proteins, protein and peptide fragments, antigens that encode ARNI or DNA and mNA can be stabilized when trapped in other supply systems, adding lipid and polymer nanodebrides, or combined with lipids or polymers. Viral vector vaccines and virus remains are also an active ingredient in vaccine development studies.
The use of DNA-based peptides, proteins, mNA or antigens, as well as oligonucleotide-based adjuvants for vaccination is limited through their inherent instability when administered systemically. Advanced formula strategies have been developed combined with a rational design of nanotransporter systems for the systemic supply of these other bioactive compounds, overcoming their immediate degradation through the nucleases, their immediate elimination, their limited mobile absorption and their effects outside target105,106.
Nanotechnology-based approaches107,108,109,110,111,112,113 have several benefits that play a key role in the progression of an effective vaccine (Table 1).
FDA-approved nanoscale delivery systems (e.g. Liposomes, polymer nanoparticles) for drug management in humans fully help to have an effect on these complex vectors in combating fatal human diseases. The fusion of bioconvergence, bioengineering and drug administration of nanotechnology is well programmed to meet unmet needs, as each of these spaces has matured on its own to the point that it can now be used to complement others in a truly extensive and rational way, rather than modestly and empirically. These nanomanagement platforms, along with newly developed techniques to achieve the right maximum targets, are expected to enable humoral and cellular-specific immune reactions of resistant antigen and expand next-generation vaccines opposed to a variety of viral diseases, adding SARS-CoV-2. The use of nanocarriers to advance vaccine progression has been based on artificial recombinant proteins or sequences of peptides of structural viral targets (e.g., S or N SARS-CoV114) or non-structural in the past known as antigens, combined with adjuvants, such as TLR agonists (e.g. CpG43, imiquimod115, Poly (I: C) 116, Monophosphoryl Lipid A (MPLA) 117 or adjuvant of glucopirans lipidil (GLA) 118Array and other immune regulators , such as montanid119 and inflammatory inducers (e.g. Chitosan120)) or protein ligands 1 inducible through retinoic acid (RIG-I) 121. In fact, our own previous findings have shown that the combined management of LRT antigens and agonists is essential for achieving a force-mediated cytotoxic and cellular immune reaction for cancer prevention and treatment43. We are now refocusing our efforts to leverage our manolene polymer nanoplatelet to expand a COVID-19 vaccine. Our nanovaccina allows us to program the localization, pharmacokinetics and co-delivery of immunomodulatory compounds, selling reactions that cannot be achieved by administering such compounds as a solution.
The use of RNA for vaccine progression is a revolutionary generation that comes to the use of a supply formula good enough for stability and, therefore, the translation capacity of this oligonucleotide at the intracellular level39,122,123. Non-replicative mRNA vaccines encode the antigen of interest, while self-amplifying RNA will lead to the translation of viral and antigenic replication machinery that will allow intracellular RNA amplification and protein expression. MRNA, DNA, VLP or other administration formulas-based vaccines have become popular candidates, especially in recent approvals of 2 small Alnylam (Ontropat (patisiran) and Givlaari (givosiran) interfering RNA products.) No mNR and DNA- The founded vaccines have been put on the market and, as a result, their protection profile in giant populations is recently unknown124.125. However, the catechic lipid nanoparticle COVID-19 (mNR-1273), which encodes a stabilized SARS-CoV-2 Protein S evolved through ModernaTX, Inc126., Entered Phase I127 clinical trials on March 16 and Phase II clinical trials on May 28.
While it is imperative to promote the progression of these immunomediated approaches, it is vital to remain in the brain because there are open vital problems similar to the progression of SARS-CoV-2 infection and has an effect on host immunity that wants to be addressed. This complex wisdom is essential, on the one hand, to elucidate the various mechanisms of the host’s immune reaction related to the neutralization of the virus and/or the eradication of inflamed cells. However, on the other hand, it will also wait for the final results received when implemented massively in the target population. As a result, the effect of sex and age on the virus’s ability to modulate the host’s immune reaction should be fully taken into account, as well as the effect of SARS-CoV-2 infection on the immunity of patients with chronic diseases, namely diabetes, hypertension, chronic diseases. obstructive pulmonary disease (COPD), among others.
In the early stages of SARS-CoV infection, macrophages exhibit a pro-inflammatory phenotype (M1) and nitric oxide production, IL-6, IL-8, IL-1, ROS, MCP-1, CXCL-10 and TNF mediator. the host fights the virus, but also promotes lung injuries128. Meanwhile, anti-inflammatory macrophages (M2) are active and will heal once the pathogen is eliminated, restoring lung tissue128. Patients with SARS-CoV infection were found to have a faster buildup of S neutralizing antibody titers than those who recovered from SARS-CoV129. In addition, studies of inflamed mice and monkeys with SARS-CoV have reported an agreement between induction of the immune reminiscence of SARS-CoV-express and the accumulation of upstream lung inflammation46,130. However, T cells have also been connected to the murine coverage opposed to this infection131,132. A recent study128 showed that vaccination of SARS-CoV-inflamed macaques with a modified Ankara vaccine virus (MVA) encoding SARS-CoV glucoprotein S (ADS-MVA) was able to improve the production of the anti-SARS-CoV S antibody – protein neutralizing, however, these animals had varying degrees of alveolar damage. This express immunity of S-IgG was connected to minimize viral load, along with an improvement in the infiltration of inflammatory monocytes/macrophages into the lungs and the nullification of the reaction of curative macrophages in the early stages of infection128. In addition, the prepress medRxiv published through Wu et al. indicates that the degrees of express anti-S antibodies were correlated with lymphopenia and disease severity in patients with COVID-19133. Other studies have reported that S-express immunity has effectively contributed to viral elimination and laboratory animals protected from SARS-CoV134,135 infection.
Therefore, systematic studies must address the SARS-CoV-2 immune-mediated impact at different stages of the disease, correlating those findings associated to cellular and humoral responses with their impact on pulmonary immunopathology, but also taking into consideration the type of vaccine and the viral strain used for infections.
Depending on the vaccine and related nature of the antigen used to trigger a specific immune response, it is important to demonstrate the extension of the response triggered under COVID-19 disease upon immunization (Fig. 6). These required preclinical studies are currently limited as it was previously shown that the CoV S protein does not bind to mouse counterpart due to structural differences already identified between the human and mouse ACE2136. However, even if the information available on preclinical studies performed to specifically address immune-mediated response against COVID-19 is limited, including in non-human primate models, several mouse models previously developed to address the development of therapeutic and prophylactic solutions against SARS-CoV infection can now be explored to advance drug discovery and development against COVID-19. Examples include the ACE2, TMPRSS2 and STAT1 knockout mouse models. ACE2137,138 and TMPRSS286,138 have been identified as being related to SARS-CoV-2 entry into cells, while STAT1139,140 favours progressive lung disease by increasing viral replication in the lungs. These experimental mouse models are particularly suitable for the study of SARS-CoV-2 pathogenesis and development of new therapeutic options. BALB/c and C57BL/6 mice may be used to characterize the immune response against potential vaccine candidates, even in the absence of disease141. Particularly relevant for characterizing the human immune response triggered by SARS-CoV-2 infection and therefore to guide the design of effective and safe vaccines may be the transgenic human leucocyte antigen (HLA) class I and class II mouse models142 harbouring HLA genes covering high percentages of human population. Additional tools to support preclinical development include the transgenic mouse model bearing human ACE2 for SARS-CoV-2 infection (SARS-CoV-2 hACE2), including the recently developed by Bao et al.51 and Jiang et al.143, as well as, by the Jackson Laboratories following a model previously established by the Pearlman research group144,145. Moreover, mice that support the development of immune cells following the engraftment of human peripheral blood mononuclear cells (PBMC)146,147 or human hematopoietic stem cells (HSC)148 should also be considered.
These assays include the evaluation of dendritic cell (DC) and T cell function upon immunization by flow cytometry and quantification of levels of antigen-specific binding and neutralizing antibodies at different time-points. These studies are still limited by the mouse models of SARS disease currently available, but different options are emerging as potentially useful for the study of SARS-CoV-2 infection mechanisms and COVID-19 vaccine development. DC, dendritic cell; FACS, fluorescence-activated cell sortin; ELISA, enzyme-linked immunosorbent assay; Ig, immunoglobulins (Ig); hACE2, human angiotensin-converting enzyme 2; HLA, human leukocyte antigen; PBMC, peripheral blood mononuclear cell.
Advantages
Protection of entrapped bioactive molecules from harsh conditions, such as the gastrointestinal environment, inactivation from blood components and recognition from reticuloendothelial system107.
Potential for vaccine delivery through routes alternative to parenteral administration108.
Increase the delivery of antigens to antigen presenting cells, providing improved immune responses compared to those obtained with the soluble counterparts109.
Biodegradability and biocompatibility can be controlled.
The formulation processes the stability of bioactive agents.
Availability of translational production procedures 110.
Limits
Vaccine development process—requires validated methods to clinically evaluate new vaccine strategies110.
A complicated translation to the clinic due to the superior load and complex procedures for chemistry, production and controls (CMC) 111.
Suitable sterilization methodologies for clinical use of parenteral administrations112,113.
Risk of denaturation of the incorporated biomolecules by the organic solvents, shear stress or temperature used during particle formulation111,113.
Low entrapment efficiencies for some macromolecules.
Required characterization of biodistribution profile to anticipate safety concerns of cationic nanoparticles, accumulation in off-target sites and possible effects of burst release of the components.
The homology of MERS-CoV, SARS-CoV, and the newly emerging SARS-CoV-2, as well as the similar clinical development of these diseases that starts by a pulmonary inflammatory state followed by fibrosis and subsequent compromise of lung function, are driving the attention of the scientific and clinical communities to the use of immune-modulators, which has already achieved remarkable success149. The immune-mediated targets vary between the different types of viruses, as in some infections this pathogen has a major role in host tissue/organ damage, while in others it is the systemic and local immune activation mounted upon infection that impairs host repair function due to hyperstimulation149.
Scientific and clinical communities have primarily explored two approaches to balanced immunity to reduce viral load, while preventing terminal failure of the inflamed organ90. The first includes the management of immune suppressants150 to decrease hyperinflamation induced by a viral infection, which in turn can cause damage to the inflamed area90. Corticosteroids are widely used to suppress lung inflammation and decrease the threat of lung damage in critical patients with viral respiratory infections, such as those induced by MERS-CoV32,151 and SARS-CoV152. However, the true threat of benefit underlying corticosteroid use is not yet clear. In fact, corticosteroids also restrict immune responses and would possibly counter viral elimination, as has been observed in others with MERS-CoV31,153 infection. Given this, at the same time that EDS evolved in patients with SARS-CoV-2 infection, corticosteroid remedy advice for these patients is still controversial, and has recently been addressed in ongoing clinical trials (NCT04244591) 13.154. However, the effects of the RECOVERY trial imply that dexamethasone can also be used to decrease the mortality rate of patients requiring respiratory assistance69.
The timing of the healing technique is the use of immune enhancers, such as cytokines, immune checkpoint inhibitors, signaling proteins, antimicrobial peptides and PRR ligands. The main goal is to eliminate the virus by stimulating the host’s innate and adaptive immune responses opposed to the virus.
Immunosuppression, mainly lymphocytopenia, is identified as one of the main reasons for increased morbidity and mortality sepsis158, expanding patients’ vulnerability to bacterial or viral infections159. One of the main hypotheses of this immunosuppression sepsis is the increased expression of immune checkpoints156, such as scheduled death 1 (PD-1) and scheduled death ligand 1 (PD-L1), which play a very important role in mobile T depletion. 160 septic patients. Preclinical and clinical studies have shown that inhibition of these immune checkpoint molecules can be opposed to sepsis-induced immunosuppression, triumph over lymphocytopenia, and therefore improve host resistance to infection161. These effects recommend that PD-1/PDL-1 inhibition is a prospective remedy for SARS-CoV-2-induced sepsis, and anti-PD-1 blocking antibodies are being studied lately, either as remote agents or in mixture with thymosin. which has also been shown to decrease mortality in these patients (NCT04268537). In addition, the priming and proliferation of T DC mobiles treated with anti-PD-L1 induced proliferation162. Therefore, blocking PD-1 related to a vaccine would possibly also be considered as in long-term attempts.
Additional approaches focus on cutting cytokine secretion. Cytokines are protein mediators that provide very important signals for key biological processes, adding mobile immunity, mobile proliferation and inflammation, wound healing and repair, mobile migration, fibrosis and angiogenesis163. High rates of transformer beta-1 expansion (TGF-1) 26.27 were detected in SARS patients, which were related to the progression of pulmonary fibrosis and the relief of apoptosis from inflamed phones with SARS-CoV164. Similar consequences of higher grades of TGF-1 were discovered in inflamed patients with SARS-CoV-2. This suggests that directing pro-inflammatory cytokines that induce pulmonary fibrosis would possibly be helpful. One of these characteristics of the remedy is pyrfenidon, for which other mechanisms have been recommended for its activity. Specifically, it reduces the degrees of proteins and cytokines related to fibrosis, as well as the accumulation of extramobileular matrix in reaction to TGF-1 and the platelet-derived expansion substance (CEF) 165. The effect of pyrfenidon is recently being studied in a clinical trial (NCT04282902) taking into account in the past reported encouraging effects opposed to idiopathic pulmonary fibrosis, in addition to its pronounced anti-inflammatory and antioxidant effects. In addition, they have an effect on TGF: elimination in the general service of T-mobiles should also be taken into account in these patients, as it would possibly restrict T-mobile-regulated immunosuppression (Treg) 166.
Unlike what has been observed in relation to TGF-1 overexpression in patients inflamed with SARS-CoV and MERS-CoV, research into immune gene expression patterns revealed descending regulation of IFN-35.36 genes. The SARS-CoV virus does not cause activation of the IFN-97 pathway, which plays a role in reducing viral replication and early dissemination167, in addition to the overall stimulant effect on the host’s immune system.168 As a result, several ongoing clinical trials are exploring the efficacy and protection of other IFN subtypes for PATIENTS with COVID-19 as healing and prophylactic agents (NCT04254874 , NCT04293887, NCT04315948).
In addition to this passive management of IFN, approaches of choice to induce TLR3 and TLR7 stimulation are promising. These are upstream transmembrary regulatory points that, when detecting an express model, such as a single-stranded and bicatenary RNA virus, will induce transcription of pro-inflammatory cytokines, adding IFN91, extending the host’s ability to the pathogen.169
TLR establishes innate and adaptive immune reactions because not only activate the innate immune system, but can also determine the nature of the adaptive immune reaction through the ascending regulation of CMH in DC, in addition to the secretion of co-stimulating molecules and the release of inflammatory procykines This procedure leads to the differentiation of CD4 T cells into Th11 cells , which in turn produces IFN-N, and lead to an elegant replacement of IgM antibodies to IgG2 through B170 cells. Therefore, an ongoing clinical trial in China (ChiCTR200029776) evaluates the healing effect of triggering TLR signaling pathways in patients with COVID-19 with a bicatenary RNA analogue [Poly (I: C)].
Another immune technique to treat COVID-19 is based on the use of endogenous molecules of the innate immune formula, such as defensins. Defensins are a circle of relatives of endogenous antibiotic peptides with a broad spectrum of antimicrobial and antiviral activity, vital for the functioning of the innate defense formula171. In the past, it has been observed that the treatment of SARS-CoV-infected mice with defensin causes alterations in the profile of cytokines in the pulmonary parenchyma, but does not appear to be pulmonary pathology, inhibits proliferation or eliminates the sarS-CoV virus. However, intranasal management of defensine particularly protected mice from SARS-CoV172 infection, making it potentially favorable for high-risk groups.
Since the end of 2019, methods for the progression of the SARS-CoV-274173 vaccine have been followed. Most of these approaches target surface-exposed glycoprotein S or protein S (full-duration or express subunits) to induce a strong neutralizing effect by causing express T-cell responses and neutralizing antibodies174,175. As of April 8, 2020, there were 115 vaccine candidates, 37 of whom have not been shown as active as opposed to SARS-CoV-2 infection, and 73 of the 78 reported as active, are at a very early level with no additional preclinical studies.97
Additional Tables 4a, (b) summarizes candidate vaccines developed to defeat SARS-CoV-2 infection, the efficacy and protection of which are being evaluated at a preclinical stage. It is moderate to expect that even applicants who effectively demonstrate a protective profile and abundant ability to modulate the immunity of the opposite host to this virus will take about a year to begin Phase I clinical trials.
Treatment characteristics that can also be used as opposed to SARS-CoV-2 come with virus-binding molecules, inhibitors that target express enzymes related to replication and viral transcription, small molecule inhibitors that target helipads, proteases, or other proteins that are very important for the survival of the virus. cell protease and endocytosis inhibitors, RNAith, antisent and ribozymatic RNA, neutralizing antibodies, mAb opposite host receptor or RBD S1, antiviral peptide targeted at S2 and herbal products17,176,177. At the moment, labor reintegration, lopinavir / ritonavir alone or in combination with IFN-, mAb or convalescent plasma are among the maximum studied remedy characteristics opposite SARS-CoV-2173.178. In addition, the characterization of mAb-induced effects in COVID-19 patients would possibly also advance the progression of vaccines and increasingly rapid diagnoses179. However, each of these equipment will need to be evaluated in terms of clinical efficacy and protection before being used to treat inflamed patients. Additional tables 5a, d list complex healing approaches under preclinical progression for SARS-CoV-2.
Preventing new SARS-CoV-2 infections would possibly be the most effective technique, not only to save COVID-19 but also to block the spread of the virus worldwide. As the SARS-CoV-2 virus has been recently identified, primary efforts are being made to expand vaccines. As of June 30, 48 clinical trials were already comparing the efficacy of COVID-19 vaccines (Additional Table 6a). A technique developed through ModernaTX, Inc. uses lipid nanoparticles (LNPs) that encapsulate mRN-1273 that encodes the full-length sarS-CoV-2 S protein (NCT04283461). Cells that express this viral protein will be able to provide the SARS-CoV-2 antigen recognized by T cells and induce an immune reaction opposed to the virus. This can be an effective and safe technique, as it does not use viral particles, but delivers an RNA that can be expressed through immune and non-immune cells, leading to the provision of the MCH Class I and MHC Class II antigen. In addition, the encapsulation of viral mRNA in the NRL will protect mRNA from degradation and delivery effectiveness.180 The Modern PRESS releaseTX181 issued on May 18 announced an intermediate knowledge of this ongoing Phase I trial for the mNR-1273 vaccine, indicating that the vaccine was sometimes well tolerated and safe, and led to the production of neutralizing antibodies in 8 initial patients enrolled in this study , two weeks after receiving the candidate dose of COVID-19.
A new recombinant vaccine opposed to CoV was proposed, a vector of adenovirus type five, also called Adfive-nCoV (NCT04313127) through CanSino Biologics Inc. Protein 2 S., based in Tianjin. The ChAdOx1 nCoV-19 (NCT04324606) evolved through oxford University. also a clinically evolved adenovirus vector vaccine, which has been explored as a vaccine opposed to other infectious diseases, such as influenza, tuberculosis, Chikungunya virus (CHIKV), Zika, meningitis B and plague.
There are other clinical trials that explore the use of genetically modified activated immune cells that recognize SARS-CoV-2 antigens (Additional Table 6a). The Genoinmune Medical Institute in Shenzhen has designed minigenes (exon gene fragments) based on several viral genes, which are introduced into synthetic antigen cells (APAC) using a lentiviral vector (NCT04299724). When injected into the patient, APAC turns on the T cells and generates an immune reaction opposed to the virus. In addition, LV-SMENP-DC, also from the Shenzhen Genoimmune Medical Institute, is a modified DC that expresses viral antigens (NCT04276896). These DCs are used to activate ex vivo cytotoxic T cells (CTLs). Both changed D.C. and activated CTL will be injected into patients. On April 6, 2020, INOVIO Pharmaceuticals announced the launch of the Phase 1 clinical trial of its INO-4800 DNA plasma vaccine encoding electroporation-administered S protein (NCT04336410), founded in its past-exploited generation for Lassa, Nipah, HIV, phyllovirus, human papillomavirus, Zika and hepatitis B. Another prophylactic technique to prevent COVID-19 disease in adults exposed to the virus includes breathing in PUL-042, which is a 2/6/9182 TLR agonist. By binding to these LRT, PUL-042 can activate immune cells, such as herbal killer cells (NK), macrophages and CDs, and stimulate lung epithelial cells to produce points opposite photogenic infection.183
Although promising, these clinical trials are recently being recruited for Phase I or Phase II, and efficacy and protection in human patients have not yet been confirmed.
Most clinical studies check existing immunotherapies or reuse of existing medicines for the remedy of patients with COVID-19 (additional 6a-d tables). As of June 30, there were 217 registered clinical trials using immunomodulators opposite COVID-19, while more than 476 were reading the additional price of drug reuse.
Immunoglobulin injection from convalescent patients was tested to induce an express immune reaction as opposed to SARS-COV-2 (NCT04264858). Other trials attempt to induce a broad immune reaction through non-express activation of the immune system. For example, a mixture of a popular remedy with an anti-PD-1 antibody (NCT04268537) is being clinically investigated. Another example is recombinant IFN-2, an immunomodulator approved for the treatment of viral infections, such as hepatitis B and C, and for the treatment of other cancers, such as metastatic melanoma (NCT04293887) 184.185.
Other clinical studies are testing other anti-inflammatory agents to decrease lung inflammation (pneumonia), the leading cause of death in patients with COVID-19. These come with antibodies aimed at inflammatory factors, such as IL-6 and the supplement’s C5 protein, or the CD24Fc conjugate that blocks LRT activation. Two clinical studies use the antiangiogenic drug bevacizumab (mAb anti-VEGF) to decrease pulmonary edema. Another antibody in clinical progression is meplazumab, which blocks the binding of the SARS-CoV-2 S protein to the CD147 molecule in human cells, thus reducing the ability of viral infection34. Other immunosuppressive agents, such as the inhibitor JAK1/JAK2 baricitinib and the antimalarial drug hydroxychloroquine sulfate, are also being tested. Although optimal remedy regimens are still being studied, doctors report other dosages and schedules.
Few clinical studies explore mobile therapies, such as NK mobile phones to help and immune reaction (NCT04280224), while others use mesenchymatous mobile phones, which can facilitate tissue regeneration and immune suppression.186
Faced with the tragic figures coming every day from around the world on 18 March 2020, the Director-General of the United Nations announced unprecedented action in which foreign cooperation made possible the concept of the solidarity trial. The World Health Organization (WHO) 187 announced on 27 March 2020 that forty-five countries were already contributing, and many others had expressed interest in joining this historical trial, the main objective of which is to temporarily perceive the protection and efficacy of remdesivir, lopinavir/ritonavir. lopinavir / ritonavir with IFN-1a and chloroquine or hydroxychloroquine188. The contribution of knowledge received through this multi-country trial in a concerted manner allows for direct comparison between these medicines, which will particularly reduce the time required to provide transparent and physically powerful knowledge to demonstrate which medicines will be effective as opposed to COVID-19.
The COVID-19 pandemic has spread to 213 countries and territories, and the number of cases reported as of 30 June 2020 surpasses 8.5 million worldwide. More than 5.6 million people recovered from SARS-CoV-2 infection, but 506 thousand people were defeated by this virus. The number of new cases continuously rises.
The seriousness of the stage has already reshaped our society. The reports come from peak countries that show the enormous commitment of the government, clinical and clinical communities to make concerted efforts to bring local populations to the pandemic.
The reorientation of studies in many educational and commercial establishments has also been recently implemented, taking advantage of existing wisdom and reveling in the opposite combat of past infectious diseases that can bring new responses to the COVID-19 pipeline. History also shows that these crises create unique opportunities for the advancement of new technologies or the flexible use of existing technologies.
The SARS-CoV-2 is indeed a new strain of coronavirus, and even if the scientific community is rapidly gaining tremendous knowledge about this virus, the world population has not yet acquired immunity. The development of an effective vaccine will be particularly important to protect high-risk patients, taking into account their decaying immune function. Therefore, the development of a COVID-19 vaccine suitable for mass immunization is urgent and companies and research institutes have already reported the development of more than 115 vaccine candidates. Researchers worldwide are exploiting platform technologies previously developed to control CoV infections, as well as other diseases, such as HIV, influenza, Zika, Ebola, plague, tuberculosis and meningitis. The development of these vaccine candidates is expected to be particularly fast as their safety and efficacy in modulating host immune response have already been attested, even if against other agents that may not exactly present the same pathogenesis but that modulate physiological functions in a similar manner. However, despite the diverse platform technologies available to produce these vaccines, all developers agree that it is highly unlikely that a vaccine will be available for worldwide use in less than 12 months, in particular taking into account that the development of an Ebola vaccine took 5 years and a mumps vaccine took 4 years in a record time.
The tremendous advances in molecular engineering and biotechnology for the last years have led to engineered biotech compounds, such as peptide and protein antigens, multiple copies of antigen-encoding mRNA, in addition to gene regulators of immune cell function, such as siRNA to suppress the expression of immunosuppression-related genes.
However, as candidates move towards clinical investigation, it becomes clear that their biological effects depend on the development of a tool able to attain their transport across biological barriers. In fact, low response rate of patients has been related to the limited intrinsic immunogenicity of antigens, and therefore, the added value of adjuvants, such as TLR ligands, are commonly considered to overcome sub-optimal efficacy. However, oligonucleotides, such as the TLR ligands CpG or Poly (I:C), or siRNA and mRNA candidates, are limited by low stability under physiological conditions, off-target effects and limited cellular uptake189. The systemic effect of oligonucleotides demands the design of safe and effective delivery systems to target and cross plasma membranes, but also to escape from endosomal compartments into the cytoplasm. The key to unlock their potential has pointed nanomedicines as an approach able to guarantee the target selectivity required for their efficacy, while ensuring patients’ safety. Accordingly, nanotechnology-based systems incorporating combinations of antigen epitopes and adjuvants are being developed to improve vaccine delivery. These nano-based vaccines orchestrate a broad immunity by modulating B cell-mediated responses towards an increased and fast production of high-affinity neutralizing antibodies upon re-encountering cognate antigens, but also by allowing an adequate activation and expansion of T cell-function directed, for example, to the destruction of virus-infected cells. Nanotechnology-based strategies also constitute a potentially useful tool to enhance the stability and improve the pharmacokinetics of therapeutic antibodies. The entrapment of antibody derivatives has been explored to improve their delivery and endosomal escape, which will result in improved intracellular antigen recognition190. It has also been shown that the entrapment of immune checkpoint monoclonal antibody modulators by polymeric nanoparticles improved the immune-mediated responses to these immunotherapies, such as to the agonist anti-OX40191 and to the anti-CTLA4 blocker192. Nanoscale delivery systems improve the delivery of active compounds to specific cells and tissues, and decrease adverse effects cause by systemic administration, for example of FDA-approved cytokines, such as TNF-α193 and IL-2194.
The similarity between the infection mechanisms of SARS-CoV-2 and other CoVs and HIV also indicates that drugs already clinically-approved to target different steps of the infection pathway constitute promising potential solutions against COVID-19. Accordingly, ritonavir and lopinavir are currently under consideration. However, caution should be taken due to distinct HIV and SARS proteases, which can limit the specificity of their therapeutic activity. Chloroquine phosphate and hydroxychloroquine sulfate, as well as remdesivir may lead to better clinical outcomes as these will probably have a broad-spectrum activity by eventually inhibiting SARS-CoV-2 cell entry and the RNA polymerase, respectively195. Time is also crucial; vaccines are intended for administration before the infection (or as intervention in case of a therapeutic vaccine), antivirals need to be administered as soon as possible after infection, whereas immunostimulants or -inhibitors could be given later.
Despite lack of medical evidence, the severe respiratory symptoms presented by an 80-year old critically ill COVID-19 patient were rapidly attenuated upon the administration of recombinant human erythropoietin (EPO)196. Previous preclinical studies reported the effect of EPO on septic cases197,198, and on the inhibition of pro-inflammatory cytokine expression and increase of B cells, as well as CD8+ and CD4+ T cells in circulation199. Even though this patient also received hydroxychloroquine, oseltamivir and lopinavir/ritonavir, these effects were observed following EPO and red blood cell transfusion, which led to an increase in the levels of haemoglobin. Clinical studies on the use of EPO in COVID-19 patients are required, but its use should be carefully considered, for example in patients with anaemia associated with renal chronic disease due to already known side effects such as thrombotic events.
It is important to bear in mind that unfortunately, we are still far from having a full picture of the pathophysiology of this dangerous disease, including its long-term implications on individuals that did not experience the severe form of this infection. What the clinical and scientific communities first thought of as being an infectious disease that, similarly to other CoV-related infections, would mostly affect the respiratory tract, soon became a multifaceted pathology, which major features include the massive accumulation of blood clots. It is now clear that the SARS-CoV-2 infection causes heart attacks, coronary-related kidney damage, severe stroke, including in young people with no previous history of cardiovascular disease, being all related to extensive clot formation. In addition, several countries, such as Italy200, UK201, Canada202 and USA202, reported the hospitalization of children and young adults presenting severe Kawasaki-like disease related to COVID-19, showing inflammation in medium-size blood vessels, rash, fever and, in some cases, shock. Children are accepted to be the least affected by this disease, but this emerging link between SARS-CoV-2 infection and this rare inflammatory condition associated with systemic blood vessel damage in COVID-19 positive young patients, is raising awareness towards the urgent need for collecting data covering clinical outcomes and presentations of this emerging phenomenon. Clinicians and scientist worldwide are driving concerted efforts to correlate the behaviour of the immune system components with SARS-CoV-2 infection, as well as to decipher genes related to high-risk of disease severity, fundamental to point out children who are at high-risk and help on clarifying the chaotic/uncontrolled immunity found in adults.
The search for life-saving solutions to treat COVID-19 patients or achieve the control of SARS-CoV-2 transmission is crucial to win the race against the rapid transmission of this virus, and regulatory bodies worldwide have joined efforts to respond to this outbreak by providing new mechanisms to support a faster development and approval of the most promising therapeutics and vaccine candidates. However, it is fundamental to simultaneously ensure that adequate measures are being taken to thoroughly demonstrate their safety and efficacy. For example, the European Medicines Agency (EMA) released on 27 March an updated version of the Guidance on the management of clinical trials during COVID-19203, namely addressing communication with the governmental authorities, informed consent and distribution channels of investigational medicines. The guidance further includes information regarding the distribution of diagnosis tests, safety reporting and auditing.
The COVID-19 pandemic reminds us of the devastating effect that emerging diseases have had on our history on the progression of effective vaccines that have particularly reduced the burden of these infections. As WHO204 recognizes, only access to safe drinking water has a greater effect on disease and death. Vaccine movements have made their voices heard as opposed to immunization programmes around the world, which has already increased the onset of rare diseases in developed countries. Therefore, recent measures taken by society to restrict the serious economic, social and cultural consequences of the COVID-19 pandemic have the potential to further strengthen national immunization programmes. Unfortunately, physical estrangement and blockade measures have already seriously compromised the vaccination of young people who oppose other vital infectious diseases, namely measles, polio, diphtheria, tetanus and whooping cough205. WHO says one hundred million young people are expected to lose the measles vaccine due to COVID-19 blockade. Therefore, as the pandemic begins to succeed in a containment phase in several countries, it is vital to analyze the knowledge gathered over the past five months and the expected has an effect on prolonged blockade, also examining the possible effects on social and economic levels. . It is also vital to investigate the procedures of medical care and the remedy of patients affected by other diseases who have been abruptly discontinued by the COVID-19 pandemic. For example, canceled procedures that restrict the diagnosis of the disease and cancer treatment programs that have been affected, such as surgeries, chemotherapy, or radiation therapy. In light of these facts, several countries are already taking prudent steps to facilitate the blocking of COVID-19, in order to control the spread of SARS-CoV-2 among the population.
The control of highly contagious and life-threatening infectious diseases has shaped human history over the centuries, and the COVID-19 pandemic will be no exception. However, we are now at a time when very complex technological resources are available, possibly our weapon to replace the course of this pandemic. Therefore, it is vital to invest in fitness systems and fundamental and cutting-edge science to locate diagnostic and healing solutions. It is encouraging to see collaborative efforts in all sectors involved in the global fitness generation ecosystem. We only hope that these concepts will resonate once this pandemic is us.
R.S.-F. and H.F.F. We thank the following donors for their beneficiary: the allocation of MultiNano-MBM through the Ministry of Health of Israel and the Foundation for Science and Technology-Ministry of Science, Technology and Higher Ensino (FCT-MCTES) as a component of EuroNanoMed- II (ENMed / 0051/2016); “La Caixa” Foundation as a component of Health 2019 Research Appeal (LCF / PR / HR19 / 52160021; NanoPanther), CaixaImpulse (CF01-00014; CoVax). In addition, R.S.-F. thanks to the monetary beneficiary of the Proof of Concept (PoC) grant from the European Research Council (ERC) (862580; 3DCanPredict) and the ERC Advanced grant (835227; 3DBrainStrom), The Israel Science Foundation (1969/18), The Melanoma Research Alliance: established the Researcher Award (615808), the President of the Israeli Cancer Research Fund (ICRF) (PROF-18-682), the Morris Kahn Foundation and the NOFAR Incentive Program at COVID-19 through the Israel Innovation Authority, published through The Merck Group. D.v. thanks to the Rothschild Foundation (IL) for investing his doctoral fellowship. Before Christ. FCT-MCTES (PhD Fellowship SFRH / BD / 131969/2017).
Institute for Drug Research (iMed.ULisboa), Faculty of Pharmacy, Lisbon University, Lisbon, Portugal
Helena F. Florindo, Rita C. Acercio and Barbara Carreira
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Ron Kleiner, Daniella Vaskovich-Koubi, Eilam Yeini, Galia Tiram, Yulia Liubomirski and Ronit Satchi-Fainaro
Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
Ronit Satchi Fainaro
R.S.-F. he is Director of the Board of Directors of Teva Pharmaceutical Industries Ltd.
Information on the Peer Review Nature Nanotechnology thank you Erik De Clercq and the other unnamed reviewers for their contribution to the peer review of this work.
Editor Springer Nature’s note remains impartial in relation to jurisdictional claims on published maps and institutional affiliations.
Additional tables 1 to 6 and ref. 1–22.
Reprints and permits
Received: April 11, 2020
Accepted: June 2020
Published: 10 July 2020
DOI: https://doi.org/10.1038/s41565-020-0732-3