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Multiple groups of scientists are trying to develop a coronavirus vaccine but they are not yet being fruitful. What challenges or difficulties are there in the process that slowing down and/or causing failure in development of vaccine?
There are multiple challenges presented, and many of those are not limited to coronavirus vaccine.
As mentioned above, it just takes time. Before a vaccine can be used in patients, clinical trials must be performed to validate the safety and efficiency of the vaccine candidate. A Clinical trial includes three phases, which again, just takes time.
But to really answer your question, what are some challenges of developing a vaccine?
To begin with, from the perspective of lab research, we first need to develop a vaccine candidate. What protein on the virus should we take as an antigen? There are many many proteins on the virus, and for CoV, we know it is a protein called Spike protein. It is the neutralizing target on the virus. Which means, when an antibody bound to this site, it could prevent the virus from infecting the cells. Okay, then we have to know, do we need to do something to this protein to make a vaccine? For example, when we try to manufacture this protein into a vaccine, what if the protein is degraded? Or it somehow becomes a 'bad' protein that simply cannot stimulate immune responses in human? These are just some examples of roadblocks of developing vaccine.
Let's suppose we finally work those out. Then what's next? Each candidate vaccine needs to be tested in animals before going into human clinical trial. This step is time-consuming.
Now we are finally ready to start clinical trials. According to FDA, the vaccine for human trials (also for each drug) needs to be produced under Good Manufacturing Practices (GMP). It's basically a standard operating procedure to make sure that the vaccine candidate can be manufactured in a large-scale, quality-controlled manner. There are many many challenges, like how to purify the protein? How to scale-up production. This is partly of the reason why the first vaccine in trial in USA is an mRNA, and in China is a DNA, both of which does not require complicated protein purification.
As you can see, the list of challenges can go on and on. But there are scientists and doctors working diligently on it. Hopefully we'll get there.
Vaccine development is not as easy as just inject some inactivated virus as:
Vaccine can have side effects such as inflammatory reactions. So for a good vaccine the side effects must be negligible or within a tolerable limit.
Vaccine may not induce immune response. It may be ignored by the immune system as just some random debris. So a good vaccine must be recognised as a foreign object by the immune system.
The vaccine may be not so specific. I.e, the immune response may have high cross-reactivity that may undesirably interfere with some undesired biomolecule or unrelated process.
The desired activity of the vaccine may be too specific, i. e. on slightest genestic variation of the virus, the vaccine may fail.
An attenuated strain as a vaccine, may have a possibility to revive and form revertant strains. A good vaccine must be safe from pathogenicity
The immune response may not last long. For a good vaccine the immunity have to last long.
The shelfed vaccine must have some stability with time, temperature, transport etc. If the vaccine quickly loses its activity then it wont stay usable.
Some individuals may not respond to the vaccine, such as depending upon genetic preconditions. So a good vaccine must elicit immune response to a wider range of population.
There may be challenges regarding isolation, preservation and maintaining a desired 3-D structure of the protein from virus.
- Any research-process tend to be slow, and unpredicted problems may appear at any steps.
These are likely to make any vaccine development as conceptually slow, tedious, testing dependent, and safety concerned.
Polio vaccination: Past, present and future
The ideal vaccine
Eliminating vaccine cross-reactivity
Vaccine efficacy article on Wikipedia
Immunology is very complex, with so many interactions that prediction is difficult.
For example, some vaccine candidates will probably be designed to provoke an immune response against the proteins on the spikes of the virus. If that protein is similar to proteins already existing naturally in the body, then the vaccine wont work, because immune cells that attack the self are destroyed during their maturation.
A vaccine needs to be able to neutralize the virus (bind to it and masking from entering the cell) with high affinity. Now the virus is a large complex structure, so it is not immediately clear how to design a vaccine that can achieve that.
Screening antibodies from recovered patients might be a good idea, but it takes effort and time. What is more, the antibodies isolated from those patients may not be optimal for a vaccine, and some rational design based on those antibodies might be needed.
Another challenge is how to get a sustained level of vaccine proteins in the human body. The cutting-edge in the field right now is to use mRNA instead of proteins. You can read something about Moderna, which spearheaded this effort in the pandemic. But we still do not know what those RNAs are doing and where they are going in the body, so it takes many experiments and creativity to send those mRNAs into the human body so it can function properly.
To make a vaccine, you also need very strict production standard known GMP to make sure that the product is clean, pure and safe. This is not very easy and not every lab in the world can do.
COVID-19 Vaccines: Should We Fear ADE?
Might COVID-19 vaccines sensitize humans to antibody-dependent enhanced (ADE) breakthrough infections? This is unlikely because coronavirus diseases in humans lack the clinical, epidemiological, biological, or pathological attributes of ADE disease exemplified by dengue viruses (DENV). In contrast to DENV, SARS and MERS CoVs predominantly infect respiratory epithelium, not macrophages. Severe disease centers on older persons with preexisting conditions and not infants or individuals with previous coronavirus infections. Live virus challenge of animals given SARS or MERS vaccines resulted in vaccine hypersensitivity reactions (VAH), similar to those in humans given inactivated measles or respiratory syncytial virus vaccines. Safe and effective COVID-19 vaccines must avoid VAH.
Keywords: SARS-CoV-2 T cells antibody-dependent enhancement (ADE) coronavirus dengue dengue hemorrhagic fever hypersensitivity immunopathology vaccine vaccine adverse events.
What's So Hard About Developing A COVID-19 Vaccine? We Asked A Scientist.
As the coronavirus pandemic continues to spread around the globe, the best hope for truly getting it under control is a vaccine that would protect people from contracting COVID-19. Scientists in the U.S., China, the U.K. and elsewhere are racing to develop a vaccine and there have been some promising signs that one of the many vaccine candidates under development may prove effective against the virus.
In the U.S., President Donald Trump has predicted a vaccine will arrive before the end of the year . Dr. Anthony Fauci , director of the National Institutes of Health’s National Institute of Allergy and Infectious Disease, has said it’s a question of “when and not if” a vaccine against this coronavirus , known as SARS-CoV-2, will be developed, and also predicted that could happen before year’s end.
With COVID-19 taking lives and crushing economies around the world, stopping the spread would provide tremendous relief. But the progress of science is characterized more by failure than success. Researchers are working on almost 200 potential vaccines for this coronavirus, and there’s no guarantee any of them will ever work, let alone one that’s ready for wide use within months.
Creating a safe, effective vaccine that quickly would be unprecedented. In addition, no one has ever attempted to produce a new vaccine , distribute it to every corner of the world and carry out an immunization campaign on this scale and with this much speed.
To get a better understanding of the challenges facing vaccine researchers, HuffPost spoke to Vincent Racaniello , a professor of microbiology and immunology at Columbia University’s Vagelos College of Physicians and Surgeons in New York.
Is it realistic to expect a vaccine for the novel coronavirus by this winter?
No, I think it’s highly unrealistic to expect a vaccine by the end of 2020. We haven’t made any vaccine in that short of time. That would be a year from January, when we first saw circulation in the U.S. Eighteen months is optimistic. What would be more realistic, in my view, would be next summer. But, you know, vaccines can take five to 10 years and longer. The polio vaccine took 50 years to develop. Certainly, we’ve advanced in our technology so we can do it faster now, but I would say, no, the end of this year is completely not feasible, in my view. However, I would love to be surprised.
How would a SARS-CoV-2 vaccine work to prevent people from becoming ill?
What vaccines do is they’re introduced into you ― they can be injected, or they can be taken orally, or through any number of other routes ― and they turn on your immune system to make a response to the virus that’s in question, in this case SARS-CoV-2, without making you sick. Then you have an immune response and, most importantly, your immune response comes with a wonderful feature called “memory,” so it remembers what it’s encountered so that whenever it sees that agent again, it will respond. So that’s what a vaccine tries to do ― it tries to produce immune memory without any of the pathogenic or disease consequences of a real infection.
Is this similar to what the human immune system does itself when it fights off infections?
Absolutely. If you get influenza or a common cold virus or any other virus ― if you survive, of course ― then you have immune memory, and then whenever you encounter the virus again, you should mount a nice response and you should prevent infection entirely. You won’t even know that you’ve encountered the virus.
What are the primary challenges to developing new vaccines for any disease?
There are many, but the main one is understanding what’s needed to protect you from infection. We’ve been talking very generally about the immune response but, in fact, there are different components. There are cells and proteins involved, and so we need to know which is important for the particular virus. That’s one of the reasons that it took 50 years to make a polio vaccine, because people had to figure out what was important. Now, for this new virus, we don’t have the time to do that, so we’re making a lot of assumptions about what’s important, and we hope that they’re right.
How do governments, pharmaceutical companies, academic institutions and scientists decide how to prioritize the development of vaccines for some diseases over others?
I hate to say, this is very sad and this is an indictment of the whole system for making vaccines, but the main priority is profit.
The companies that make vaccines, they’re all for-profit companies and they need to see that they can make a profit off of their vaccine. So all the vaccines that we have are there because many, many people are infected with viruses like influenza, measles, mumps, rubella, shingles and polio. They infect a lot of people and the companies can make money from them.
However, there are many diseases out there that are far less prevalent but nevertheless they kill people. Companies aren’t interested in making vaccines for those diseases because there’s no profit to be made. I think that’s a fatal flaw with our vaccine system that has to be fixed and it’s why we don’t have a vaccine ready for this particular virus. We could’ve, but no company was interested. Same for antiviral medications. That’s why we’re in this situation we’re in right now.
One could think of creative ways to get around that. Governments can get involved, for sure. We’re hobbled in this country by the political paralysis of our government and its unwillingness to invest in science completely, so that’s stymied that. Now, since this SARS-CoV-2 has emerged, there are new nonprofits that have popped up saying, “We’re going to fund vaccine development.” In the end, it’s just a matter of someone raising money, and there’s plenty of money out there to do this. Think about the money we’re spending on recovery in the U.S. ― trillions. If a fraction of that money had been spent on developing a vaccine, we’d be out of this problem.
There are no vaccines available for any strains of the coronavirus, including the one that causes COVID-19. Why is that?
After SARS-1 in 2003, it went away. We were able to stop it. The virus disappeared. So most companies said, “We’re not interested in making a vaccine. There’s no market.” But a few academics went ahead and they made an experimental SARS vaccine, but it never got beyond that because there’s no financial support.
It’s not hard. In fact, it would’ve been not very hard to make a vaccine that could protect against many coronaviruses that come out of bats. But again, no financial backing for that and, even more, no research support. In the U.S., the NIH was not willing to support that kind of fundamental research because its budget is too limited.
There are many novel coronavirus vaccine candidates in development. What will determine which, if any, are used?
Unfortunately, they’re mostly not even in phase 1 in people. A handful are in phase 1 and a couple in phase 2. Those have been pushed and those are going to be the ones that finish first, so they’ll have an advantage. Now, whether they work or not is important, obviously, so if they don’t work, that’s the end of that and the others are going to have to catch up.
The others are not even out of the laboratory. Some of those may never get out of the lab. It may turn out there are too many problems developing those. Others might, but as companies see that other companies have a head start, they might decide not to put resources in it because they’ll lose money. Many of these companies have never made vaccines before. Very few companies have, and I think that’s a factor. If you haven’t made a vaccine, you’re going to have more problems because you don’t know what you’re doing.
All of those things are factors, and then of course production is a factor. I hope we have more than two vaccines because I don’t see how you could make 7 billion vaccine doses with just two companies. I think we need at least 10 vaccines to be able to cover the whole planet.
What are the potential downsides of deploying vaccines developed quickly during an emergency like the SARS-CoV-2 pandemic?
We could take a lesson from the polio vaccine in the 1950s. It was only about 50% effective, yet that’s what they had so they went ahead with it. And that meant that a lot of kids whose parents lined them up for shots weren’t protected. It also meant that companies had rushed production. In fact, a lot of kids got polio from that early vaccine because it wasn’t made properly. You could imagine that these early SARS-CoV-2 vaccines, because they’re rushed through, are not as optimal as they could be and they’re not going to be as effective. In most cases, the vaccine candidates are not infectious so I’m not too worried about them causing the actual disease.
If you try to scale up vaccine production for hundreds of millions of doses, things could go wrong. Normally, we take a lot of time to do this. Everyone is being assured that we’re doing things in a safe way, but I think there’s still room for things to go wrong when you rush things.
People say, “Well, if they’re rushing it, I’m not going to take it,” and I think that’s a valid concern. What I often say is if you rush a vaccine and there’s a problem and you hurt people, then you will never get people to take it for many years. Once there’s a negative view of a vaccine because of some side effect, then people are very reluctant to take it. We have to make very sure that this is safe. We cannot make shortcuts. We have to test it in enough people ― thousands of people ― to make sure there are no side effects.
If a novel coronavirus vaccine were developed, what would need to happen for it to be deployed widely and safely?
You need a lot of doses, first of all, because I do not want it to be distributed only to wealthy countries. That’s not the point of vaccines. The developed nations are making the vaccine, but they have to understand they have to share it with everyone, and I do hope that happens here. That’s my primary concern.
You have to make enough of it. If we only have one vaccine that turns out to work, it’s going to be really hard to make enough doses for everyone. Another issue is these vaccines are going to have to be cold, probably frozen, and not everywhere has that capability. Finally, what about the delivery? Most of these vaccines need to be injected. That means you need at least 7 billion needles. I don’t even know if we have 7 billion needles in the world, so I hope someone’s thinking about that ahead of time. And you need people to inject them. You can’t just do it yourself. You need a trained health care worker, which isn’t available everywhere.
Has a vaccination campaign of this scale ever been attempted?
No, never. We’ve never had to immunize everyone. We’ve always had select groups, like for childhood disease where we do mass campaigns. There is no precedent for this, for having to immunize every person on the planet.
Old And New Challenges In The Development Of Vaccines To Protect Against Infectious Diseases
Vaccines are one of the most effective tools in protecting humans from infectious diseases globally and the only health intervention capable of eradicating a disease altogether. It is estimated that the global use of vaccines is preventing 2 to 3 million infectious disease deaths every year. Vaccines to .
Vaccines are one of the most effective tools in protecting humans from infectious diseases globally and the only health intervention capable of eradicating a disease altogether. It is estimated that the global use of vaccines is preventing 2 to 3 million infectious disease deaths every year. Vaccines to prevent bacterial and viral disease have shown not only direct benefits but also indirect ones such as providing herd immunity or having a significant preventative impact on the generation of antimicrobial resistance (AMR). Despite these enormous positive public health impacts, the complexity of designing and developing safe and effective vaccines, licensure and recommendation requirements, access and global distribution are not widely appreciated by the general public or even health care professionals. In addition, with an increasing understanding of the fundamental protective vaccine-induced immune responses, we are now moving into the area of “designer vaccines” with novel technologies and approaches to not only protect against infectious diseases but also cancer.
In this Research Topic, we aim to address the general knowledge gap with regard to vaccines and to provide a comprehensive resource for researchers and health professionals with an interest in infectious diseases and vaccines. Furthermore, we aim to highlight new areas of research that will enable improved design and development of infectious disease vaccines that have eluded us in the past. Finally, we aim to highlight new approaches to protect the most vulnerable, neonates, from deadly diseases by maternal immunization.
We propose to invite submissions summarizing the history of vaccine impact with emphasis on describing the benefit-risk of vaccines, challenges in vaccine recommendations and global access or implementation. We also look for submissions that address challenges in vaccine development that will highlight the multidisciplinary approach to complex vaccine development. In addition to these background submissions, we anticipate submissions that will focus on recent discoveries improving our understanding of protective host immune responses to vaccination, or novel vaccine antigen designs or delivery modalities enabling the development of infectious disease vaccines to protect against respiratory syncytial virus (RSV), cytomegalovirus (CMV), Mycobacterium tuberculosis (TB), or other bacterial diseases associated with antimicrobial resistance such as Escherichia coli (E. coli) or Clostridium difficile (C. diff). Finally, we propose to invite submissions that address vaccine protection of neonates from vaccine preventable devastating diseases such as Group B streptococcus (GBS).
This Research Topic is open to original articles, research notes, and reviews.
Topic Editor Dr. Kathrin Jansen is employed by company Pfizer. All other Topic Editors declare no competing interests with regards to the Research Topic subject.
Keywords: Bacterial And Viral Vaccines, Maternal Immunization, Vaccine Challenges, Vaccine Benefits, Infectious Diseases
Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.
Molecular Basis of Coronavirus Virulence and Vaccine Development
Virus vaccines have to be immunogenic, sufficiently stable, safe, and suitable to induce long-lasting immunity. To meet these requirements, vaccine studies need to provide a comprehensive understanding of (i) the protective roles of antiviral B and T-cell-mediated immune responses, (ii) the complexity and plasticity of major viral antigens, and (iii) virus molecular biology and pathogenesis. There are many types of vaccines including subunit vaccines, whole-inactivated virus, vectored, and live-attenuated virus vaccines, each of which featuring specific advantages and limitations. While nonliving virus vaccines have clear advantages in being safe and stable, they may cause side effects and be less efficacious compared to live-attenuated virus vaccines. In most cases, the latter induce long-lasting immunity but they may require special safety measures to prevent reversion to highly virulent viruses following vaccination. The chapter summarizes the recent progress in the development of coronavirus (CoV) vaccines, focusing on two zoonotic CoVs, the severe acute respiratory syndrome CoV (SARS-CoV), and the Middle East respiratory syndrome CoV, both of which cause deadly disease and epidemics in humans. The development of attenuated virus vaccines to combat infections caused by highly pathogenic CoVs was largely based on the identification and characterization of viral virulence proteins that, for example, interfere with the innate and adaptive immune response or are involved in interactions with specific cell types, such as macrophages, dendritic and epithelial cells, and T lymphocytes, thereby modulating antiviral host responses and viral pathogenesis and potentially resulting in deleterious side effects following vaccination.
Keywords: Biosafety Human coronaviruses Immune response Innate immune response Live-attenuated vaccines Protection Vaccines Virulence.
© 2016 Elsevier Inc. All rights reserved.
Genome structure of human CoVs.…
Genome structure of human CoVs. Each bar represents the genomic organization of a…
Innate immunity signaling pathways affected…
Innate immunity signaling pathways affected by human CoV proteins. The main pathways leading…
Multidomain structure of CoV nonstructural…
Multidomain structure of CoV nonstructural protein nsp3. The approximate boundaries of each domain…
Inhibitors of p38 MAPK activation…
Inhibitors of p38 MAPK activation protects mice infected with recombinant SARS-CoV. (A) Syntenin…
In order to ensure that the threat of COVID-19 is eliminated, it is critical that a coordinated and cooperative approach is taken which includes the collaboration between several international organizations to ensure that a process to ensure that sufficient financing and fair distribution of the vaccine supply is available. GAVI, the Vaccine Alliance is one such organization, which is a global public-private partnership to ensure that individuals from developing countries, particularly children, have access to immunizations (63). It is also part of the recent Global Vaccine Summit, which allocated funding for COVID-19 vaccine development and also to healthcare systems of GAVI-eligible countries and adequate supply for developing countries. In addition, Bill and Melinda Gates Foundation (BMGF) have allocated $250 million toward development of vaccines and for supporting the health care systems of Sub-Saharan Africa and other developing countries (64). Coalition for Epidemic Preparedness Innovations (CEPI) is a foundation that is involved in financing vaccine development and has launched COVID-19 Vaccine Global Access Facility (COVAX) in order allow for equal access of COVID-19 vaccines for countries (65). Lastly, the WHO is very much involved in all aspects of COVID-19 pandemic including ensuring vital equipment and personal protective equipment (PPE) such as masks and medical gowns for health care workers, research for COVID-19 vaccines, providing accurate information pertaining to COVID-19 and coordinating with countries for a response to COVID-19 amongst others (66). The WHO is also documenting data from vaccine candidates in its Draft Landscape of COVID-19 vaccine being updated periodically (28). Additionally, cooperation from individual countries is also equally important in the fight against COVID-19.
What are the difficulties/challenges against developing a coronavirus vaccine? - Biology
Whilst all of the countries that are part of COVAX have the infrastructure needed to get pallets of vaccines off cargo planes and into refrigerated warehouses, the next steps can be more complicated.
“Ghana, the first country to receive COVAX doses, has had a good record of distributing doses”, says Gian Gandhi, UNICEF’s global COVAX coordinator, “but other countries, such as those in Francophone West Africa, have found it difficult to muster the resources needed to divide up doses and distribute them throughout their territory to the towns and villages where they’re needed. This means that, in many poorer countries, most doses are being distributed in large urban centres”.
“We want to ensure that no-one misses out”, says Mr. Gandhi, “but, in the short term, the concentration of doses in cities at least means that the vaccination of health and other frontline workers in urban areas, where the higher population density puts them at a higher risk of exposure, is being prioritized”.
3) More funding is needed to help rollout in the poorest countries
One way to speed up the vaccine rollout, and the delivery from urban warehouses to remote areas is, quite simply, cash. “Funding is a perennial concern, even in pandemic response”, says Ms. Abad-Vergara. “To continue providing vaccines to its 190 members, COVAX needs at least $3.2 billion in 2021. The faster that this funding target is achieved, the faster that vaccines can get into people’s arms.”
Contributions from several countries, particularly the EU, the UK and the US have gone a long way to closing the vaccine funding gap. However, funding for the delivery of those vaccines is more problematic.
UNICEF estimates that an additional $2 billion is needed to help the poorest 92 countries to pay for essentials such as fridges, health worker training, expenses for vaccinators, and fuel for the refrigerated delivery trucks, and is calling on donors to make $510m of this available immediately as part of a humanitarian appeal to address urgent needs.
4) Richer countries should share excess doses
COVAX is finding itself in competition with individual countries doing direct deals with pharmaceutical companies, putting extra pressure on the available supply of COVID-19 vaccines. At the same time, richer countries may find themselves with an over-supply of doses.
The current ‘me first’ approach will ultimately cost more, in terms of lives Diane Abad-Vergara, COVAX communication focal point, WHO
“We’re calling on these countries to share their excess doses, and engage with COVAX and UNICEF as soon as possible”, says Mr. Gandhi, “because it will take some legal, administrative and operational gymnastics to get them to where they’re needed. Unfortunately, we’re not currently seeing too many high-income countries willing to share”.
“The current ‘me first’ approach favours those who can pay most and will ultimately cost more financially, and in terms of lives”, warns Ms. Abad-Vergara. “But it’s important to note that bilateral deals do not prevent a country from either receiving doses or contributing to COVAX, particularly through dose-sharing”.
5) Vaccine hesitancy: a continued cause for concern
Despite the overwhelming evidence that vaccination saves lives, vaccine hesitancy, which exists in every country, is still a problem that needs to be constantly addressed.
This phenomenon is partly driven by misinformation surrounding all aspects of COVID-19, which was a concern even before a global health emergency was declared and, in May, the UN launched the Verified campaign, which fights lies and distorted messages, with trusted, accurate information surrounding the crisis.
“Throughout the pandemic there has been a huge amount of misinformation swirling around”, says Ms. Abad-Vergara. "WHO is working hard to combat it, as well as building trust in vaccines, and engaging different communities”.
We've so far found with coronavirus that those infected have had different antibody responses, some weak, some strong.
The ABC has received many questions around how long immunity lasts and whether someone can be reinfected.
So is antibody response critical to whether or not a vaccine is going to work?
To answer this we have to go back to what we know about coronaviruses that cause the common cold, according to Professor Frazer.
"Yes, you get antibodies after a [cold] infection, and yes it lasts for a while, but it's not lifelong. sort of months rather than years," he said.
"I think it would be fair to say that the natural immunity that you get after infection from this coronavirus is probably going to turn out like the coronaviruses we've seen in the past.
"There will be some natural protection over a period of months, maybe even years, but it won't be lifelong.
"The good news is that if you get reinfected with the virus a second time some months down the track, there will probably be enough immunity there to stop you becoming seriously ill."
COVID-19 vaccines: challenges and future prospects
The vaccine development effort over the globe for the COVID-19 pandemic is unprecedented, in terms of scale, speed, and supply chain. It is made possible to have a safe and effective vaccine available by the end of the year 2020, for the more vulnerable group of the population and hopefully in the first half of 2021 to all the others. Operation Warp Speed program was introduced in US to fast-track vaccine development. Moderna’s mRNA vaccine and AstraZeneca/University of Oxford’s AZD1222 vaccine are part of this program. Classical clinical efficacy trials of vaccines usually enroll thousands or tens of thousands of healthy participants. However, to accelerate the COVID-19 vaccine development, clinical trial phases were combined, and smaller population was enrolled. This is a noteworthy concern when the vaccine is supposed to be given to people throughout the world, there could be emergence of unknown side-effects in the larger population, which were previously not witnessed in smaller groups during short-term trials. It is important to consider whether there was an appropriate demographic consideration in the design of the clinical trials including, different races, varying age groups and those with comorbidities, as the exclusion of these may lead to unforeseen outcomes upon vaccinating these individuals when the vaccine is released for public use.
The production teams of the vaccine candidates have stated to be under pressure to develop a vaccine within few months as compared to the conventional process of 10 years. With a fast-track process, post-marketing surveillance turns out to be important. Post-marketing surveillance would ensure that the vaccines are observed for side effects when administered in diverse populations. The foremost ethical concern is to find a safe and effective vaccine but at the same time not exposing clinical trial participants to avoidable risks .
Fast-tracking of vaccines may turn unfavorable as it could result in ineffective vaccine and may only provide partial or no immunity to some vaccinated persons. Although it is assumed that there will be thorough inspection of the vaccine candidates for safety and efficacy from the scientific community before vaccine is released for administration into the public. It is important to consider the recent small trials of the Russian vaccine Sputnik V as well as the Chinese vaccine candidates. Both Russia and China have begun the mass rollout of state-sponsored vaccine candidates with limited data. In the perspective of a public health emergency of international concerns, such shortened regulatory pathways and fast-tracked implementations are still commonly regarded as experimental interventions and are unique. However, to preserve public trust in vaccines, it is vital that complete transparency in all facets of vaccine development is available.
Due to increased demand and limited supply of vaccines, several countries including the US, India, and Europe have decided that the vaccines will be provided first to their own citizens. However, questions are being raised concerning the ethics associated with fair allocation. Though AstraZeneca has announced a collaboration with Serum Institute of India to provide an adequate number of doses to low and middle-income countries, it will be interesting how the allocation will be done when the vaccine candidates are approved and becomes available. It is also crucial to prioritize certain groups of people for vaccine allotment including, health care workers, immunocompromised individuals, those with comorbidities, the elderly, and those with lower socioeconomic status to guarantee distributive justice. There are also worries that the political pressure to hasten the development and approval processes, may result in an ineffective vaccine being released to the public. Such a consequence may lead to the public being hesitant from receiving future vaccines .
To date, no trials for COVID-19 vaccine has focused on pregnant women, despite being deemed a vulnerable population by the US Centers for Disease Control and Prevention (CDC). Although there are unanswered questions regarding the safety and efficacy of COVID-19 vaccines in pregnant women, FDA-approved COVID-19 vaccines should not be refused to women solely based on their pregnancy or lactation status, when they otherwise meet the conditions for vaccination. Patient-provider discussions should also consider the patient’s individual risknefit profile concerning exposure at work or at home, risk to expose other members of their household, current health status and perceived risk of COVID-19 associated impediments . Pregnant women should get COVID-19 vaccine without delay, as the consequences of COVID-19 infections in pregnancy are equivalent or worse than in non-pregnant populations. There is potential for damage to not one but two lives, and females of childbearing potential may have heightened workplace exposure to SARS-CoV-2. Additionally, the ongoing vaccine trials should include pregnant women to test vaccine candidates’ study safety and efficacy .
Vaccine effectiveness is described as the protection provided by immunization in a defined population. It includes both direct (vaccine-induced) and indirect (population-related) protection. The effectiveness of a vaccine is proportional to its efficacy but is also influenced by the vaccine coverage, access to healthcare centers, associated costs, and other factors not directly related to the vaccine . The question is, how much efficacy is actually needed for a vaccine to be considered immunogenic? Though more research is required, preliminary research studies have revealed that efficacy of >% is desired to eradicate the infection. A preventative vaccine with an efficacy of <% will still have a major effect and may add to obliterating the virus, given proper social distancing measures. Vaccines with an efficacy below 70% may contribute to decreasing the length of infection. Another study with simulation experiments showed that to prevent a pandemic, the vaccine efficacy has to be at least 60% with 100% vaccination coverage. The vaccine efficacy threshold rises to 70% when coverage drops to 75% .
Phase III clinical trials are required for all vaccine candidates to demonstrate that they are effective and safe in a larger population. In addition, the majority of vaccine candidates currently in clinical trials are administered intramuscularly. Though this administration route induces a strong IgG response, which is believed to protect the lower respiratory tract, unlike natural infection, it does not initiate the secretory IgA responses required to protect the upper respiratory tract . Thus, most vaccines will provide protection against infection of the lower respiratory tract and not induce sterilizing immunity in the upper respiratory tract. This could lead to protection from symptomatic diseases but might still allow virus spread by infected person. Thus, a vaccine that could induce sterilizing immunity in the upper respiratory tract would be preferable to stop virus spread. Live attenuated vaccines or viral vectors that can be administered intranasally, would probably also lead to a strong mucosal immune response as well as an IgG response. Alas, very few vaccines that are appropriate for intranasal administration are undergoing development and none have made it to the clinical trials yet .
The next ethical question is, what will be the effect of the vaccine on older individuals who are at higher risk from COVID-19? According to Sinovac’s inactivated vaccine and Pfizer’s mRNA vaccine, the effect of the vaccine in older individuals is less compared to younger adults. Thus, there is a need for different vaccine formulation or a booster dose to improve immune responses in older individuals . The children usually show increased reactogenicity compared to adults. As many CVCs have fairly strong adverse effects, low-dose vaccines might be required for children, particularly for AdV and mRNA-based vaccines. Pfizer has considered this approach and accordingly reduced the reactogenicity of its mRNA vaccine in older adults, making it appropriate for children .
There is also risk of vaccine enhanced disease for inactivated vaccine candidates (VAERD) that need to be considered. The higher numbers of antibodies are unable to neutralize the virus in case of high viral load, resulting in VAERD. Furthermore, ADE has been observed with other coronaviruses including MERS-CoV and SARS-CoV and could be a risk for CVCs. ADE occurs when antibodies bind to the virus and the resulting antibody-virus complex facilitates viral entry by host macrophages instead of neutralizing the virus. However, when there is an urgent need for CVCs globally, being concerned and assessing such risks should not prevent the release of otherwise safe and effective vaccines to the public .
If there is an incidence of the adverse reaction, there should be programs in place to safeguard proper medical treatment and compensation is provided to affected individuals and records are kept for re-evaluating the safety of the vaccine(s). The accountable authorities should also ensure that an effective and fair policy is in place, for instances where vaccination is compulsory, so the public trust in the health care system is not risked. Pre-existing immunity to adenoviruses is a concern, specifically for those vaccine candidates utilizing human adenoviruses such as CanSino vaccine, as it may lead to a decreased immune response to the vaccine. AstraZeneca/Oxford’s AZD is another adenovirus-based vaccine candidate, but instead of utilizing adenovirus derived from humans, it utilizes a genetically modified chimpanzee-derived adenovirus. This effectively eliminates the concern about pre-existing immunity and thus, averts the negative impact on the immune response generated to the vaccine . Although some vaccines are approved through EUA, long-term data on vaccine safety is also crucial. The well-known case of Dengue vaccine should not be overlooked, where dengue vaccine protected individuals against virologically confirmed dengue (VCD) and severe VCD for 5 years, who had exposure to dengue prior to vaccination. There was also a higher risk of VCD and severe VCD in vaccinated individuals who were not exposed to dengue earlier . Thus, to avert such obstacles after vaccination, even after EUA approval, long-term safety and efficacy data is essential.
Furthermore, if a vaccine is approved for use but subsequently it is found to be not as effective as expected in the population, it could lead to a loss of trust in the vaccines. There are reports of few adverse effects with the Pfizer vaccine (Table (Table3) 3 )  and these recent adverse reactions were confirmed by the Finnish Medicines Agency Filmea, Finland . Thus, when an effective vaccine is launched, fewer people may be inclined to accept it, which in turn can lead to further worsening of the pandemic and a decline in the confidence in already approved and effective vaccines against infections. Hence, it is vital to building trust in the public health system by being completely transparent and reporting accurate data in a timely fashion . Thus, the ideal characteristics of CVCs described by WHO are important to consider while developing vaccines (Table (Table3) 3 ) [66, 67].
Few mild side effects of Pfizer/BioNTech COVID-19 vaccine that should not last more than a week  and Ideal COVID-19 vaccine characteristics according to WHO [64, 65]
|Few mild side effects of (Pfizer/BioNTech) COVID-19 vaccine||Ideal COVID-19 vaccine characteristics according to WHO|
|Injection Site pain||An admirable safety of vaccines throughout target population No contraindications|
|Injection Site swelling||Least adverse incidents that are weak and temporary|
|Injection Site redness||Be appropriate for administrations to all target population|
|A headache||Generate protective immunity- preferably after one shot|
|Fever||Produce protective immunity quickly after 14ꃚys|
|Chills||Vaccine with no less than 70% efficacy|
|Tiredness||Not elicit immunopathology or evidence of antibody-enhanced disease (ADE)|
|Muscle pain||Generate protection in high risk profile peoples Deliver long term protection with both humoral and cell-mediated immunity for no less than 12 months|
|Joint pain||Booster dose requirement no less than 12 months|
|Nausea||Be rapidly produced at cost or dose that permits wide-ranging use|
|Swollen lymph nodes (lymphadenopathy)||Be thermostable, to be stored at room temperature to enhance vaccine distribution and availability|
|Remote chance of Severe allergic reaction||Be administered through non-parenteral mechanisms for ease and other logistical issues|
|Be co-administered with other vaccines|
A further challenge with coronavirus vaccines is the lack of very good animal models for testing.
Following the SARS outbreak in 2003, scientists studied mice. Mice make antibodies in response to SARS infection and their immune system is well understood. But mice do not naturally develop pneumonia with SARS coronavirus infection so it is impossible to test whether a vaccine protects against disease. This can be partially overcome by using older or genetically-modified mice or by modifying the virus.
Hamsters develop lung changes on SARS infection but do not appear to get sick. Ferrets, and several monkey species, develop lung disease with SARS coronavirus but not consistently. 
In the case of tests of vaccines against SARS in animal models there were problems in developing both protective immunity and also evidence that the wrong sort of immune response could potentially cause side effects if protection against infection was incomplete. So, in tests of early SARS vaccines in ferrets and monkeys, several vaccines stimulated antibodies against the spike protein but they only protected partially against lung disease.  Also, some vaccines were associated with lung inflammation when immunised mice were later infected with the virus. 
These examples give some insight into the difficulties of producing vaccines. They show how important it is that vaccines stimulate the right immune responses and why safety tests are vital. But these are typical findings on the route to developing vaccines and there is no reason to think that it will not be possible to develop an effective vaccine to SARS-CoV-2.
Vaccine scientists will exploit existing understanding from SARS and other coronaviruses to fast-track a vaccine for COVID-19 but many challenges lie ahead.