COVID-19: advances and prospects in designing and developing vaccines, immunotherapeutics, and therapeutics
COVID-19, an emerging coronavirus infection: advances and prospects in designing and developing vaccines, immunotherapeutics, and therapeutics
Covid-19 (Coronavirus 2019) originated from Wuhan, Hubei Province, China, and became a worldwide pandemic. Vaccine efforts have been made to combat against similar coronavirus diseases, such as MERS and SARS in the past 10 years. Currently there are no vaccines for MERS and SARS, nor any antiviral treatment. Most candidate vaccines for coronavirus in development go after spike glycoprotein, or S protein, which targets antibodies. There were some participants who showed effectiveness with in vitro studies, but there are few that have evolved to “spur of the moment” clinical trials with animals and people, leading to scant functioning on treating the Covid-19 function. This scientific article focuses on constant changes with making new vaccines and therapies to treat Covid-19, and at the same time, concentrating on lesson from SARS and MERS, which can enable hard work to put an end on this developing infection.
This section basically talks about what coronavirus is, which are single type RNA that belong to the Coronaviridae viruses, that bring infection to many ailments from cold to deadly illnesses. The official name of the virus is known as “SARS-CoV-2” by CSG (Coronavirus Study Group) of International Committee on Taxonomy of Viruses (ICTV), because it is related to the sister disease, SARS. The unfolding of coronavirus, which started in China, transmitted to other countries and was declared a pandemic by WHO. There are currently no vaccines nor antiviral treatment available on combating this mysterious new coronavirus infection, but many countries are putting their best foot forward to put action on finding preventative ways to control the spread of this disease.
Developing a vaccine to combat coronavirus has become something of a Holy Grail quest, but it has become complicated on getting to that goal, mainly because they have such a complex genetic sequence. Other vaccines, immunotherapeutics, and possible drugs to try have been sought after, for other past emerging diseases, such as Zika, Ebola, Nipah, SARS, and MERS. Exploring these options to the best advantage can lead to potency, efficacy, and safety, while at the same time promoting efficiency on other research that is out there, on overcoming Covid-19. But still, there has been no confirmed vaccine or therapy, which is a work in progress.
Therapies on curbing Covid-19 are mostly based on previous lessons for treating SARS and MERS. Pharmaceuticals have shown lack of interest on resolving this deadly disease. When drugs are made during the outbreak, they only last during the outbreak. By the time a new medication or vaccine is made, there might not be any participants or clinical experiments, and a market to test the new medication.
The WHO recommends that patients will receive the following: oxygen therapy, fluid therapy, and antibiotics on preventing future bacterial infections. The WHO suggests patient quarantine confirmed or unconfirmed to have Covid-19. Drugs that have been effective on coping with Covid-19 have been the following: remdesivir, lopinavir/ritonavir alone or in combination with interferon-β, convalescent plasma, and mAbs. In any case, clniical efficacy, and safety studies must be done before these drugs can be administered for experimental use on treating Covid-19.
This article delves into how researchers have been coming up with vaccines and therapies for overcoming Covid-19, while at the same time going back to lessons learned from SARS and MERS. Both ailments can provide answers on going on the right track to put an end to this deadly zoonotic virus, known as coronavirus.
There have been many attempts on making a coronavirus vaccine. The focus is mainly on using S protein on producing antibodies. There have been proposals on relying full length S protein, S1 receptor binding domain (RBD) and using virus like partcles, DNA, or viral vectors. S protein has S1 (RBD talks to ACE-2 [angiotensin-converting enzyme 2]), and S2 acts as the middleman between virus and host cell to give out viral RNA to cytoplasm for copying. S proteins function to give off antibodies to inhibit virus from binding, but also virus uncoating the genome. S protein functions in HUGE role by activating immunity while coronavirus takes by releasing antibodies and T cell responses. Therefore, this leads to the hypothesis that S glycoprotein is a promising choice for coronavirus makeup. There is no evidence suggesting S protein immunogenicity or connecting ACE2 receptor as an important step for virus to go inside the cell through absent and present means of other protein structures. Recombinant proteins having RBD and recombinant vectors encoding RBD function on making coronavirus vaccines.
Regarding MERS, S makes IgG, along with secretory IgA. An experiment done with mice shows resident memory T-cell reaction through the nose. Similarly, the RV (rabies virus) was a viral vector along with gram-positive enhancer matrix (GEM), functioning as bacterial vector, used to make MERS S protein.
Talks of making a coronavirus vaccine to be used worldwide was looked into, after studying resemblance on T-cell epitopes with SARS and MERS, which showed ability for cross reactivity in coronaviruses. SARS shows resemblance with coronavirus, and the vaccines made for SARS can react similarly to SARS. An evaluation done on S proteins for SARS and coronavirus, showed that there were residues in the S1 subunit of S protein, which is the most important coronavirus target.
Immuno-informatics has been adopted to detect epitopes on putting into the development of COVID-19 vaccine. As an example, they used immuno-informatics to detect major cytotoxic T lymphocyte (CTL) and B-cell epitopes contained with SARS S protein. Associations with epitopes and MHC class I molecules were closely seen, through molecular dynamics simulations. From the findings, CTL epitopes connect through to MHC class I proteins through multiple hosts, implying ability on producing more immune reaction.
Researchers are currently in the process of developing a vaccine for chimpanzees. CEPI (The Coalition for Epidemic Preparedness Innovations) made it clear that they were going to implement 3 programs used to develop COVID-19 vaccines through recognized vaccine methods.
Administering monoclonal antibodies (mAbs) can lead to CoV control as a form of intervention for people exposed to the virus. Observation has shown that patients recuperating from SARS show neutralizing antibody responses. A clinical experiment shows mAbs that work on specific areas of MERS-CoV S protein. These mAbs stick to 6 specific epitope groups communicating with receptor binding, membrane fusion, and sialic acid-binding locations, which symbolize 3 crucial entry functions for MERS. In addition, passive immunization and strong neutralizing antibodies leads to solid protection in mice going through MERS. Antibody use can symbolize a revolutionary method to make more humoral protection against the new coronavirus by going after lots of S protein epitopes and functions. Cross-neutralization capacity of SARS RBD-specific neutralizing mAbs solely is on the resemblances between RBDs.
Technology enables the production of antibodies (human single-chain antibodies; Hu-scFvs) or humanized-nanobodies (single-domain antibodies, sdAb, VH/VHH) which allows going across the membrane to virus-infected cells (trans bodies). Moreover, it sticks to or disrupts biological activities of copying virus proteins, leading to inhibiting of virus copying. It is probable to produce trans bodies to CoV intracellular proteins, like papain-like proteases (PLpro), cysteine-like protease (3CLpro) or other non-structural proteins (nsps) that are important in coronavirus copying and transcription leading to safe, nonimmunogenic, very effective passive immunization of CoV participants, and treating infected patients.
Animal models for vaccine evaluation
Animal models suitable for judging vaccines (SARS and MERS) are deficient or severely limited, leading to the difficulty of vaccine development production. Development of an animal model that is efficient, and copies clinical ailment can be used to let pathogenesis be in the know, and to develop vaccines and therapeutics from coronavirus.
Efforts on early development making of animal models for SARS-CoV, except ACE2 (receptor of SARS-CoV) was a big interference on these efforts. Later, a SARS transgenic mouse model was made, through introducing hACE2 gene into the mouse genome. The first animal model used in developing MERS vaccine was rhesus macaques. Infected animals displayed clinical symptoms (increased body temperature, piloerection, cough, hunched posture, and reduced food intake). Another popular animal model for MERS is the common marmoset, where the virus triggered lethal pneumonia. Humoral and cell-mediated immunity could be identified both in rhesus macaques and common marmoset with MERS immunization.
Several tries on making animal models for MERS in the following animals: mice, hamsters, and ferrets encountered limitations because of inability for MERS to copy in respiratory tracts from these animals.
Small animals such as mice and rabbits, compared to large animal models, are the lab of choice, because of low cost, manipulation ease, and they are easily and readily available. Other research shows they are in demand to identify which models are suitable for new SARS by showing receptor affinity towards SARS and examining disease manifestations, pathologies/viral pathogenesis linked with experimental inoculation related to the virus in animals such as mice, rats, and other models, along with monitoring virus-specific immune responses and protection. This would help preclinical evaluations for potential COVID-19 vaccines and medications.
Cell culture systems
Epithelial cell lines have been extracted to see any neutralization of antibody preparation titers. Other animals included are goat and alpaca, relying on umbilical cord cells to extract S protein found in MERS and SARS. In addition, using S protein has been shown to find its way into MERS and SARS, by way of hepatoma cell lines, through “neutralizing antibodies” in patients having coronavirus.
Then, there are false virions (GFP or luciferase), which functions on testing the ability for mAbs and medications blocking Coronavirus entrance.
There are sprecific mAbs (in human or almost human form), that go after S1-RBD and non-RBD, and S2 aspect of the Coronavirus that bring about, and are currently being examined in petri dishes for virus neutralizing capability along with animal models in the area of prophylaxis and “post-exposure efficacies”.
Information regarding Coronavirus vaccines show systemic humoral or cell-mediated immune reaction by parenteral administration might not be sufficient to stop respiratory ailments. Origin of the site for Coronavirus infection is respiratory mucosa.
The main goal with clinical management is centered on relieving symptoms from the disease and providing good care. Among some therapies being considered for Covid-19 are the following: molecules sticking to the virus, inhibiting molecules going after certain enzymes associated with viral copying, transcribing, inhibiting small molecule going after helicase, crucial proteases, other virus proteins, inhibiting host cell protease , host cell endocytosis inhibitors, siRNA, anti-sense RNA and ribozyme, neutralizing antibodies, mAbs going after host receptor or interfere with S1 RBD, antiviral peptide targeting S2, and products made from natural sources.
S protein is seen as main ingredient on coming up with Coronavirus antiviral therapies like S protein inhibitors, S cleavage inhibitors, neutralizing antibodies, RBD–ACE2 blockers, siRNAs, fusion core blockers, and protease inhibitors. These therapies have shown ability in vitro and / or invo antiviral coronavirus development. On the other hand, in vitro studies with these ingredients have demonstrated efficacy, a majority do not have enough support because of animal random experiments or human participant trials, leading to little functionality for Coronavirus. Therefore, lots of support is needed to expand animal and human clinical experiments in order for specific therapies as these to be functioning in people.
Taming further spread of the Coronavirus can be based on preventative practices taken from the MERS and SARS outbreaks, along with safety measures because of its still mysterious origins. Conventional treatments for Coronavirus include the following: mechanical ventilation, ICU admission, and symptomatic and supportive care are advised for severe situations. Promising treatments for Covid-19 include the following: RNA protein making inhibiting medications, such as remdesivir, neuraminidase inhibitors, peptide (EK1), anti-inflammatory drugs, abidol, Chinese traditional medicine, such as Lianhuaqingwen and ShuFengJieDu capsules. Furthermore, clinical experiments will be needed to declare safety and efficacy on Coronavirus. A big limitation on designing Coronavirus vaccine is time. It can take significant valuable time in the form of months and years to make a Coronavirus vaccine available to the public. So, the focus should be on finding new drugs and immunotherapies that have shown a track record on overcoming viruses resembling Coronavirus.
Length of time needed to be on the lookout for the new antiviral Coronavirus drug to become mainstream can take more than a decade. As of now, a new therapeutic agent for Coronavirus is not a suitable route due to time. Another suggestion would be to redesign currently used antiviral drugs for viral ailments. These types of drugs are known to be easily obtained on the market due to pharmacokinetic and pharmacodynamic properties, solubility, stability, side effects, regulated dosage. Redesigned drugs (lopinavir/ ritonavir and interferon-1β), seen in vitro anti- MERS Coronavirus development. To evaluate redesigned drugs for Coronavirus, a regulated clinical trial experiment in combination of ritonavir boosted lopinavir and interferon-α 2b therapy has been implemented for hospital use in patients in China
Oseltamivir, a type of neuraminidase inhibitor, has been the clinical drug used for Coronavirus in cases where Covid-19 might be detected in China’s hospitals, even though there is not information demonstrating efficacy. A list of approved in vitro antiviral drugs may include the following: ribavirin, penciclovir, nitazoxanide, nafamostat, and chloroquine. These drugs were tested side by side with remdesivir and favipiravir, two broad-spectrum antiviral drugs. With the evaluated drugs, remdesivir and chloroquine were seen to be very effective on controlling COVID-19 in vitro. The study showed that 3 nucleoside analogs such as ribavirin, penciclovir, and favipiravir probably don’t have significant in vivo antiviral effects to overcome coronavirus because big dosages are needed to decrease the viral infection in vitro. Both remdesivir and chloroquine are implemented as treatment options for other ailments, and have an established safety profile. Therefore, these medications are ideal for implementing for evaluating their efficacy in patients having Coronavirus.
Breakthroughs on vaccines and therapies for SARS, MERS, and coronavirus will lead in the fight to overcome this new deadly virus. But a huge gap on resolving the problem involves putting into place rigorous preventative and safety measures because of concern for developing hospital infections. Preventative measures are the appropriate way to go about this current dilemma given considerable time needed before new vaccines and antiviral agents start showing up.
Conclusion and Future Prospects
Academics are on the lookout for possible vaccines and therapies to curb the spread of the deadly Coronavirus. To date, there are no vaccines and antiviral drugs for Coronavirus. As of right now, the best that can be done on coping with Coronavirus is tough preventative and safety measures that decrease the chance of passing on the disease. Data from an in vitro study from Covid-19 are showing positive signs, especially these 2 drugs, remdesivir and chloroquine. Researchers observed their impact on curbing the infection. Clinical experiments can be done with Coronavirus participants, as these medications have a good track record, and a consistent safety profile, which allows easier medication evaluation. S protein is an important antigen in vaccine development. Clinical data documentation on therapies for Coronavirus is scant as of now, even with pending research on enhancing prevention, treatment, and curbing the coronavirus. More research needs to be done on SARS with appropriate animal models in the following areas: close monitoring of replication, transmission, and pathogenesis.