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What is cross-immunoreactivity, and how does it impact vaccine development?

What is cross-immunoreactivity, and how does it impact vaccine development?


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What I understand about cross-immunoreactivity is that the antibody induced by one specific antigen is also fairly effective against another antigen. How would this be used for vaccine development?

Moreover, cross-immunoreactivity is related to epitopes. And how is how is cross-immunoreactivity defined among epitopes? Are variants of a specific virus hypervariable region some kinds of epitopes? What does antigenic convergence have to do with cross-immunoreactivity? Any comments or directions to further references are greatly appreciated.


Cross-immunoreactivity is just as you stated where an antibody that is specific to one antigen may recognize another antigen. I don't think this term is widely used as I see cross-reactive or broadly reactive more often. With regards to vaccines against viruses, cross-reactive immune responses are very important to establish an immune response that is effective against varying strains. Using Influenza as an example, an antibody that recognizes the HA protein of the H3N2 strain and also recognizes the HA protein of the H1N1 strain would be cross-reactive. If we had a vaccine capable of this we would not have seasonal flu.

Epitopes are specific regions on the antigen that are recognized by T cells or antibodies. They are the specific area on the protein structure that is recognized. Thus, for a response to be cross-reactive that specific structure must be present on both antigens. Epitopes could be located in any region of the protein, viruses will often have a region that is highly antigenic and highly variable to trick the immune response into focusing on the highly variable region rather than the more conserved regions.

Antigenic convergence is related to the sequence space available to the virus. Since viruses have limited space for genes the amount of possible variation is limited as a single point mutation can have a large effect on the virus. Taking this into account some predictions could be made on how the virus might evolve. If the virus is evolving in such a way that there might be conserved epitopes, those epitopes might be important for cross-reactivity. Here is a paper on antigenic convergence in Hepatitis C. http://www.nature.com/articles/srep00267

This is a paper focused on flu, but it outlines the ideas surrounding cross-reactive antibody responses. http://www.ncbi.nlm.nih.gov/pubmed/26175732


COVID-19 vaccines: The new technology that made them possible

The COVID-19 pandemic served as an unexpected proof of concept for mRNA vaccines.

Days before her 91st birthday, Margaret Keenan became the first person in the world to receive the Pfizer-BioNTech COVID-19 vaccine outside of clinical trials.

Keenan, who was sporting a polka-dot cardigan over a festive shirt, was given the first dose of a two-dose vaccine at the University Hospital Coventry in England, setting off the first mass vaccination effort against a virus that has now infected at least 70 million people worldwide and killed 1.5 million. An 81-year-old named William Shakespeare was next in line for the vaccine.

Keenan and Shakespeare are also the first humans, outside of a trial setting, to be given a vaccine that harnesses "mRNA" technology. This relatively new tech, which relies on a synthetic strand of genetic code called messenger RNA (mRNA) to prime the immune system, had not yet been approved for any previous vaccine in the world.

But the COVID-19 pandemic served as an unexpected proof of concept for mRNA vaccines, which, experts told Live Science, have the potential to dramatically reshape vaccine production in the future. In fact, two COVID-19 vaccines developed by Pfizer and Moderna, are 95% and 94.1% effective, respectively, at preventing an infection with the novel coronavirus causing COVID-19.

On Thursday (Dec. 10), a panel of experts voted and recommended that the Food and Drug Administration (FDA) grant emergency approval to Pfizer's vaccine, or permission for it to be distributed prior to full approval under emergency situations like a pandemic. The panel is set to assess Moderna's vaccine on Dec. 17. Healthcare workers and vulnerable individuals in the U.S. could receive the Pfizer vaccine as early as next week.

COVID-19 has really "laid the foundation" for rapid production of new vaccines, such as mRNA vaccines, to fight future pathogens, said Maitreyi Shivkumar, a virologist and senior lecturer in molecular biology at De Montfort University in Leicester, England. "With the technology that we've developed for SARS-CoV-2, we can very easily transfer that to other emerging pathogens."

Here's how mRNA vaccines work, and why they could make such a difference for vaccine development.


Genetic engineering applied to the development of vaccines

The simplest application of the modern genetic manipulation methods to vaccine development is the expression in microbial cells of genes from pathogens that encode surface antigens capable of inducing neutralizing antibodies in the host of the pathogen involved. This procedure has been exploited successfully for development of a vaccine against hepatitis B virus (HBV) that is now widely used. Similar approaches have been directed towards formulations for immunization against several other animal and human diseases and some of these preparations are now presently in trials. Of no less importance is the impact of biotechnology in providing reagents for fundamental studies of topics such as the determination of virulence, antigenic variation, virus receptors and the immunological response to viral antigens. The core antigen of HBV is a good example of a product of genetic engineering that is a valuable diagnostic reagent, and that is finding important use in immunological studies of particular pertinence to vaccine development.


Analysis

New polysaccharide protein conjugate vaccines focus on improving upon existing pneumococcal vaccines and the development of new shigellosis vaccines. The overall strengths and weaknesses for this approach are summarized here.

Strengths Weaknesses
Immune response to polysaccharides from bacterial surface is well characterized and known to be protective Primarily limited to production of humoral immune response which is not generally sufficient for intracellular infections
Clear regulatory pathway Application primarily limited to bacterial infections
Conjugation to protein carries acts as adjuvant Generally provides protection to narrow range of serotypes adding additional serotypes increases cost


Stages of Vaccine Development and Testing

In the United States, vaccine development and testing follow a standard set of steps. The first stages are exploratory in nature. Regulation and oversight increase as the candidate vaccine makes its way through the process.

First Steps: Laboratory and Animal Studies

Exploratory Stage

This stage involves basic laboratory research and often lasts 2-4 years. Federally funded academic and governmental scientists identify natural or synthetic antigens that might help prevent or treat a disease. These antigens could include virus-like particles, weakened viruses or bacteria, weakened bacterial toxins, or other substances derived from pathogens.

Pre-Clinical Stage

Pre-clinical studies use tissue-culture or cell-culture systems and animal testing to assess the safety of the candidate vaccine and its immunogenicity, or ability to provoke an immune response. Animal subjects may include mice and monkeys. These studies give researchers an idea of the cellular responses they might expect in humans. They may also suggest a safe starting dose for the next phase of research as well as a safe method of administering the vaccine.

Researchers may adapt the candidate vaccine during the pre-clinical state to try to make it more effective. They may also do challenge studies with the animals, meaning that they vaccinate the animals and then try to infect them with the target pathogen.

Many candidate vaccines never progress beyond this stage because they fail to produce the desired immune response. The pre-clinical stages often lasts 1-2 years and usually involves researchers in private industry.

IND Application

A sponsor, usually a private company, submits an application for an Investigational New Drug (IND) to the U.S. Food and Drug Administration. The sponsor describes the manufacturing and testing processes, summarizes the laboratory reports, and describes the proposed study. An institutional review board, representing an institution where the clinical trial will be conducted, must approve the clinical protocol. The FDA has 30 days to approve the application.

Once the IND application has been approved, the vaccine is subject to three phases of testing.

Next Steps: Clinical Studies with Human Subjects

Phase I Vaccine Trials

This first attempt to assess the candidate vaccine in humans involves a small group of adults, usually between 20-80 subjects. If the vaccine is intended for children, researchers will first test adults, and then gradually step down the age of the test subjects until they reach their target. Phase I trials may be non-blinded (also known as open-label in that the researchers and perhaps subjects know whether a vaccine or placebo is used).

The goals of Phase 1 testing are to assess the safety of the candidate vaccine and to determine the type and extent of immune response that the vaccine provokes. In a small minority of Phase 1 vaccine trials, researchers may use the challenge model, attempting to infect participants with the pathogen after the experimental group has been vaccinated. The participants in these studies are carefully monitored and conditions are carefully controlled. In some cases, an attenuated, or modified, version of the pathogen is used for the challenge.

A promising Phase 1 trial will progress to the next stage.

Phase II Vaccine Trials

A larger group of several hundred individuals participates in Phase II testing. Some of the individuals may belong to groups at risk of acquiring the disease. These trials are randomized and well controlled, and include a placebo group.

The goals of Phase II testing are to study the candidate vaccine’s safety, immunogenicity, proposed doses, schedule of immunizations, and method of delivery.

Phase III Vaccine Trials

Successful Phase II candidate vaccines move on to larger trials, involving thousands to tens of thousands of people. These Phase III tests are randomized and double blind and involve the experimental vaccine being tested against a placebo (the placebo may be a saline solution, a vaccine for another disease, or some other substance).

One Phase III goal is to assess vaccine safety in a large group of people. Certain rare side effects might not surface in the smaller groups of subjects tested in earlier phases. For example, suppose that an adverse event related to a candidate vaccine might occur in 1 of every 10,000 people. To detect a significant difference for a low-frequency event, the trial would have to include 60,000 subjects, half of them in the control, or no vaccine, group (Plotkin SA et al. Vaccines, 5 th ed. Philadelphia: Saunders, 2008).

Vaccine efficacy is tested as well. These factors might include 1) Does the candidate vaccine prevent disease? 2) Does it prevent infection with the pathogen? 3) Does it lead to production of antibodies or other types of immune responses related to the pathogen?

Next Steps: Approval and Licensure

After a successful Phase III trial, the vaccine developer will submit a Biologics License Application to the FDA. Then the FDA will inspect the factory where the vaccine will be made and approve the labeling of the vaccine.

After licensure, the FDA will continue to monitor the production of the vaccine, including inspecting facilities and reviewing the manufacturer’s tests of lots of vaccines for potency, safety and purity. The FDA has the right to conduct its own testing of manufacturers’ vaccines.

Post-Licensure Monitoring of Vaccines

A variety of systems monitor vaccines after they have been approved. They include Phase IV trials, the Vaccine Adverse Event Reporting System, and the Vaccine Safety Datalink.

Phase IV Trials

Phase IV trial are optional studies that drug companies may conduct after a vaccine is released. The manufacturer may continue to test the vaccine for safety, efficacy, and other potential uses.

VAERS

The CDC and FDA established The Vaccine Adverse Event Reporting System in 1990. The goal of VAERS, according to the CDC, is “to detect possible signals of adverse events associated with vaccines.” (A signal in this case is evidence of a possible adverse event that emerges in the data collected.) About 30,000 events are reported each year to VAERS. Between 10% and 15% of these reports describe serious medical events that result in hospitalization, life-threatening illness, disability, or death.

VAERS is a voluntary reporting system. Anyone, such as a parent, a health care provider, or friend of the patient, who suspects an association between a vaccination and an adverse event may report that event and information about it to VAERS. The CDC then investigates the event and tries to find out whether the adverse event was in fact caused by the vaccination.

The CDC states that they monitor VAERS data to

  • Detect new, unusual, or rare vaccine adverse events
  • Monitor increases in known adverse events
  • Identify potential patient risk factors for particular types of adverse events
  • Identify vaccine lots with increased numbers or types of reported adverse events
  • Assess the safety of newly licensed vaccines

Not all adverse events reported to VAERS are in fact caused by a vaccination. The two occurrences may be related in time only. And, it is probable that not all adverse events resulting from vaccination are reported to VAERS. The CDC states that many adverse events such as swelling at the injection site are underreported. Serious adverse events, according to the CDC, “are probably more likely to be reported than minor ones, especially when they occur soon after vaccination, even if they may be coincidental and related to other causes.”

VAERS has successfully identified several rare adverse events related to vaccination. Among them are

  • An intestinal problem after the first vaccine for rotavirus was introduced in 1999
  • Neurologic and gastrointestinal diseases related to yellow fever vaccine

Additionally, according to Plotkin et al., VAERS identified a need for further investigation of MMR association with a blood clotting disorder, encephalopathy after MMR, and syncope after immunization (Plotkin SA et al. Vaccines, 5 th ed. Philadelphia: Saunders, 2008).

Vaccine Safety Datalink

The CDC established this system in 1990. The VSD is a collection of linked databases containing information from large medical groups. The linked databases allow officials to gather data about vaccination among the populations served by the medical groups. Researchers can access the data by proposing studies to the CDC and having them approved.

The VSD has some drawbacks. For example, few completely unvaccinated children are listed in the database. The medical groups providing information to VSD may have patient populations that are not representative of large populations in general. Additionally, the data come not from randomized, controlled, blinded trials but from actual medical practice. Therefore, it may be difficult to control and evaluate the data.

Rapid Cycle Analysis is a program of the VSD, launched in 2005. It monitors real-time data to compare rates of adverse events in recently vaccinated people with rates among unvaccinated people. The system is used mainly to monitor new vaccines. Among the new vaccines being monitored in Rapid Cycle Analysis are the conjugated meningococcal vaccine, rotavirus vaccine, MMRV vaccine, Tdap vaccine, and the HPV vaccine. Possible associations between adverse events and vaccination are then studied further.


Genetic engineering key to developing COVID-19 vaccine

Scientists throughout the world are engaged in a herculean effort to develop a vaccine for the COVID-19 virus that has killed hundreds of thousands of people and decimated global economic activity. Without such a vaccine, normal life as we knew it before the pandemic began is unlikely to return any time soon.

The key to such a vaccine is genetic engineering, which has already resulted in the development of several successful vaccines. The active ingredients for the HPV (Human Papillomavirus Virus) vaccine, for example, are proteins produced from genetically modified bacteria. The hepatitis B vaccine, Erevebo, a vaccine for Ebola, manufactured by Merck, and the rotavirus vaccine are other examples of GE vaccines. A genetically modified rabies vaccine has been created for dogs and cattle.

With these successes in mind, experts anticipate that recent advancements in genetic engineering could substantially shorten the development timeline for a COVID-19 vaccine. It takes on average ten to fifteen years to develop a vaccine, and the most rapidly developed vaccine was a mumps immunization, which still required four years to develop from collecting viral samples to licensing a drug in 1967.

Time is clearly of the essence as there is the potential for a second wave of COVID-19 infections in the fall and winter, which would have further negative implications for public health and the global economy. The sooner we have a vaccine, the better off we’ll be, though serious logistical challenges remain.

The vaccine race begins

On January 10, 2020, Chinese scientists greatly aided the vaccine development effort by publishing the genome of the novel coronavirus, SARS-COV-2. The virus is widely believed to have originated in bats near the city of Wuhan, China. It then jumped to another species, which was consumed by humans at the wet markets of Wuhan or came into direct contact with humans in some other way.

After examining the genome, Dan Barouch, the Director of Virology and Vaccine research at Beth Israel Deaconess Medical Center in Boston, said, “I realized immediately that no one would be immune to it,” underscoring the importance of quickly developing an effective immunization.

More than 120 possible vaccines are in various stages of development throughout the world, most of which are gene based with the hope that an effective and safe vaccine can be produced by the end of 2020 or early in 2021. This would be an astonishing accomplishment. By comparison, the Ebola vaccine, which is also genetically engineered, took five years to develop.

Ken Frazier, the Chief Executive of Merck, which is working on a vaccine for COVID-19, has tried to dampen down expectations for a quick breakthrough, saying the goal to develop a vaccine within the next 12-18 months is “very aggressive. It is not something I would put out there that I would want to hold Merck to …vaccines should be tested in very large clinical trials that take several months if not years to compete. You want to make sure that when you put a vaccine into millions if not billions of people, it is safe.”

Peter Bach, the Director of the Center for Health Policy and Outcomes at Memorial Sloan Kettering, added, “To get a vaccine by 2021 would be like drawing multiple inside straights in a row.”

Genetic engineering is our best bet

To create a genetically engineered vaccine, scientists are utilizing information from the genome of the COVID-19 virus to create blueprint antigens (a toxin or other foreign substance which provokes an immune response that produces antibodies), which consists of DNA or RNA molecules that contain genetic instructions. The DNA or RNA would be injected into human cells where upon it is hoped the cell will use those instructions to create an immune response. If this type of vaccine is developed, it could offer protection for many years as the COVID-19 virus does not appear to mutate as quickly as influenza, though this critical variable could change in the future.

RNA vaccines are considered to be better at stimulating the immune system to create antibodies. They also create a more potent immune response and therefore require a lower dosage. However, they are less stable than DNA vaccines, which can withstand higher temperatures RNA vaccines, though, can be degraded by heat and thus need to be kept frozen or refrigerated.

The risks of moving quickly

Vaccine development is traditionally a lengthy process because researchers have to confirm that the drug is reasonably safe and effective. After the basic functionality of a vaccine is confirmed in a lab culture, it is tested on animals to assess its safety and determine if it provokes an immune response. If the vaccine passes that test, it is then tested on a small group of people in a phase one trial to see if it is safe, then in a phase two trial on a larger group of people. And if it passes those hurdles, a larger scale phase three trial is designed, which would involve at least 10,000 people.

These trials are necessary because trying to develop a vaccine quickly can compromise its safety and efficacy. For example, the US government rushed a mass immunization program to prevent a swine flu epidemic in 1976 that may have caused an increase in the number of reported cases of Guillain-Barre Syndrome, which can cause paralysis, respiratory arrest and death. The pandemic never materialized, though widespread public concern about flu immunization did.

Many challenges remain

Historically, the odds of producing a safe and effective vaccine are small, with just six percent of vaccines under development ever making it to the market. There are many diseases and viruses for which there are no vaccines (for example HIV/AIDS, Zika, Epstein-Barr and the common cold, among many others), even though great efforts have been made to develop them. Therefore, despite the gigantic efforts of drug companies and governments to produce a COVID-19 vaccine in the shortest possible period, there is no guarantee they will be successful.

Soumya Swaminathan, the chief scientist for the World Health Organization said that an “optimistic scenario” is one in which tens of millions of doses could be produced and initially distributed to health care workers. Mass immunizations could begin in 2022, but to inoculate the world and “defeat” COVID-19 could take four to five years. She added, however, that this outcome “depended upon whether the virus mutates, whether it becomes more or less virulent, more or less transmittable.”


Vaccines and immunization: What is vaccination?

Vaccination is a simple, safe, and effective way of protecting people against harmful diseases, before they come into contact with them. It uses your body&rsquos natural defenses to build resistance to specific infections and makes your immune system stronger.

Vaccines train your immune system to create antibodies, just as it does when it&rsquos exposed to a disease. However, because vaccines contain only killed or weakened forms of germs like viruses or bacteria, they do not cause the disease or put you at risk of its complications.

Most vaccines are given by an injection, but some are given orally (by mouth) or sprayed into the nose.

Vaccination is a safe and effective way to prevent disease and save lives &ndash now more than ever. Today there are vaccines available to protect against at least 20 diseases, such as diphtheria, tetanus, pertussis, influenza and measles. Together, these vaccines save the lives of up to 3 million people every year.

When we get vaccinated, we aren&rsquot just protecting ourselves, but also those around us. Some people, like those who are seriously ill, are advised not to get certain vaccines &ndash so they depend on the rest of us to get vaccinated and help reduce the spread of disease.

During the COVID-19 pandemic, vaccination continues to be critically important. The pandemic has caused a decline in the number of children receiving routine immunizations, which could lead to an increase in illness and death from preventable diseases. WHO has urged countries to ensure that essential immunization and health services continue, despite the challenges posed by COVID-19. More information about the importance of vaccines is available here.

Vaccines reduce risks of getting a disease by working with your body&rsquos natural defenses to build protection. When you get a vaccine, your immune system responds. It:

Recognizes the invading germ, such as the virus or bacteria.

Produces antibodies. Antibodies are proteins produced naturally by the immune system to fight disease.

Remembers the disease and how to fight it. If you are then exposed to the germ in the future, your immune system can quickly destroy it before you become unwell.

The vaccine is therefore a safe and clever way to produce an immune response in the body, without causing illness.

Our immune systems are designed to remember. Once exposed to one or more doses of a vaccine, we typically remain protected against a disease for years, decades or even a lifetime. This is what makes vaccines so effective. Rather than treating a disease after it occurs, vaccines prevent us in the first instance from getting sick.

Vaccines work by training and preparing the body&rsquos natural defences &ndash the immune system &ndash to recognize and fight off viruses and bacteria. If the body is exposed to those disease-causing pathogens later, it will be ready to destroy them quickly &ndash which prevents illness.

When a person gets vaccinated against a disease, their risk of infection is also reduced &ndash so they&rsquore also less likely to transmit the virus or bacteria to others. As more people in a community get vaccinated, fewer people remain vulnerable, and there is less possibility for an infected person to pass the pathogen on to another person. Lowering the possibility for a pathogen to circulate in the community protects those who cannot be vaccinated (due to health conditions, like allergies, or their age) from the disease targeted by the vaccine.

'Herd immunity', also known as 'population immunity', is the indirect protection from an infectious disease that happens when immunity develops in a population either through vaccination or through previous infection. Herd immunity does not mean unvaccinated or individuals who have not previously been infected are themselves immune. Instead, herd immunity exists when individuals who are not immune, but live in a community with a high proportion of immunity, have a reduced risk of disease as compared to non-immune individuals living in a community with a small proportion of immunity.

In communities with high immunity, the non-immune people have a lower risk of disease than they otherwise would, but their reduced risk results from the immunity of people in the community in which they are living (i.e. herd immunity) not because they are personally immune. Even after herd immunity is first reached and a reduced risk of disease among unimmunized people is observed, this risk will keep falling if vaccination coverage continues to increase. When vaccine coverage is very high, the risk of disease among those who are non-immune can become similar to those who are truly immune.

WHO supports achieving 'herd immunity' through vaccination, not by allowing a disease to spread through a population, as this would result in unnecessary cases and deaths.

For COVID-19, a new disease causing a global pandemic, many vaccines are in development and some are in the early phase of rollout, having demonstrated safety and efficacy against disease. The proportion of the population that must be vaccinated against COVID-19 to begin inducing herd immunity is not known. This is an important area of research and will likely vary according to the community, the vaccine, the populations prioritized for vaccination, and other factors.

Herd immunity is an important attribute of vaccines against polio, rotavirus, pneumococcus, Haemophilus influenzae type B, yellow fever, meningococcus and numerous other vaccine preventable diseases. Yet it is an approach that only works for vaccine-preventable diseases with an element of person-to-person spread. For example, tetanus is caught from bacteria in the environment, not from other people, so those who are unimmunized are not protected from the disease even if most of the rest of the community is vaccinated.

Without vaccines, we are at risk of serious illness and disability from diseases like measles, meningitis, pneumonia, tetanus and polio. Many of these diseases can be life-threatening. WHO estimates that vaccines save between 2 and 3 million lives every year.

Although some diseases may have become uncommon, the germs that cause them continue to circulate in some or all parts of the world. In today&rsquos world, infectious diseases can easily cross borders, and infect anyone who is not protected

Two key reasons to get vaccinated are to protect ourselves and to protect those around us. Because not everyone can be vaccinated &ndash including very young babies, those who are seriously ill or have certain allergies &ndash they depend on others being vaccinated to ensure they are also safe from vaccine-preventable diseases.

  • Cervical cancer
  • Cholera
  • COVID-19
  • Diphtheria
  • Hepatitis B
  • Influenza
  • Japanese encephalitis
  • Measles
  • Meningitis
  • Mumps
  • Pertussis
  • Pneumonia
  • Polio
  • Rabies
  • Rotavirus
  • Rubella
  • Tetanus
  • Typhoid
  • Varicella
  • Yellow fever

Some other vaccines are currently under development or being piloted, including those that protect against Ebola or malaria, but are not yet widely available globally.

Not all of these vaccinations may be needed in your country. Some may only be given prior to travel, in areas of risk, or to people in high-risk occupations. Talk to your healthcare worker to find out what vaccinations are needed for you and your family.

Should my daughter get vaccinated against human papillomavirus (HPV)?

Virtually all cervical cancer cases start with a sexually transmitted HPV infection. If given before exposure to the virus, vaccination offers the best protection against this disease. Following vaccination, reductions of up to 90% in HPV infections in teenage girls and young women have been demonstrated by studies conducted in Australia, Belgium, Germany, New Zealand, Sweden, the United Kingdom and the United States of America.

In studies, the HPV vaccine has been shown to be safe and effective. WHO recommends that all girls aged 9&ndash14 years receive 2 doses of the vaccine, alongside cervical cancer screening later in life.

Vaccines protect us throughout life and at different ages, from birth to childhood, as teenagers and into old age. In most countries you will be given a vaccination card that tells you what vaccines you or your child have had and when the next vaccines or booster doses are due. It is important to make sure that all these vaccines are up to date.

If we delay vaccination, we are at risk of getting seriously sick. If we wait until we think we may be exposed to a serious illness &ndash like during a disease outbreak &ndash there may not be enough time for the vaccine to work and to receive all the recommended doses.

Why does vaccination start at such a young age?

Young children can be exposed to diseases in their daily life from many different places and people, and this can put them at serious risk. The WHO-recommended vaccination schedule is designed to protect infants and young children as early as possible. Infants and young children are often at the greatest risk from diseases because their immune systems are not yet fully developed, and their bodies are less able to fight off infection. It is therefore very important that children are vaccinated against diseases at the recommended time.

I didn't vaccinate my child at the recommended time. Is it too late to catch up?

For most vaccines, it&rsquos never too late to catch up. Talk to your healthcare worker about how to get any missed vaccination doses for yourself or your child.

Nearly everyone can get vaccinated. However, because of some medical conditions, some people should not get certain vaccines, or should wait before getting them. These conditions can include:

Chronic illnesses or treatments (like chemotherapy) that affect the immune system

Severe and life-threatening allergies to vaccine ingredients, which are very rare

If you have severe illness and a high fever on the day of vaccination.

These factors often vary for each vaccine. If you&rsquore not sure if you or your child should get a particular vaccine, talk to your health worker. They can help you make an informed choice about vaccination for you or your child.

The most commonly used vaccines have been around for decades, with millions of people receiving them safely every year. As with all medicines, every vaccine must go through extensive and rigorous testing to ensure it is safe before it can be introduced in a country.

An experimental vaccine is first tested in animals to evaluate its safety and potential to prevent disease. It is then tested in human clinical trials, in three phases:

  • In phase I, the vaccine is given to a small number of volunteers to assess its safety, confirm it generates an immune response, and determine the right dosage.
  • In phase II, the vaccine is usually given hundreds of volunteers, who are closely monitored for any side effects, to further assess its ability to generate an immune response. In this phase, data are also collected whenever possible on disease outcomes, but usually not in large enough numbers to have a clear picture of the effect of the vaccine on disease. Participants in this phase have the same characteristics (such as age and sex) as the people for whom the vaccine is intended. In this phase, some volunteers receive the vaccine and others do not, which allows comparisons to be made and conclusions drawn about the vaccine.
  • In phase III, the vaccine is given to thousands of volunteers &ndash some of whom receive the investigational vaccine, and some of whom do not, just like in phase II trials. Data from both groups is carefully compared to see if the vaccine is safe and effective against the disease it is designed to protect against.

Once the results of clinical trials are available, a series of steps is required, including reviews of efficacy, safety, and manufacturing for regulatory and public health policy approvals, before a vaccine may be introduced into a national immunization programme.

Following the introduction of a vaccine, close monitoring continues to detect any unexpected adverse side effects and further assess effectiveness in the routine use setting among even larger numbers of people to continue assessing how best to use the vaccine for the greatest protective impact. More information about vaccine development and safety is available here.


Kathrin Jansen, PhD

Senior Vice President,
Head of Vaccine Research and Development

Kathrin U. Jansen, PhD, is Senior Vice President and Head of Vaccine Research and Development at Pfizer Inc, and a member of Pfizer’s Worldwide Research and Development leadership team. Dr. Jansen oversees a fully integrated, global vaccines research and development organization, with responsibilities ranging from discovery to registration and post-marketing commitments of first-in-class or best-in-class vaccines to prevent or treat diseases of significant unmet medical need. More recent accomplishments are the global licensures of Prev(e)nar13® to prevent pneumococcal diseases and the development and licensure of Trumenba®, the first vaccine licensed in the United States to prevent invasive disease caused by Neisseria meningitidis serogroup B.

Dr. Jansen received her doctoral degree in microbiology, biochemistry & genetics from Phillips Universitaet, Marburg, Germany. Following completion of her formal training, she continued her postdoctoral training at Cornell University working on the structure and function of the acetylcholine receptor. She then joined the Glaxo Institute for Molecular Biology in Geneva, Switzerland, where she focused on basic studies of a receptor believed to be a drug target to treat allergies. Dr. Jansen was appointed an Adjunct Professor at the University of Pennsylvania – School of Medicine in 2010.

Before the Wyeth acquisition by Pfizer in 2009, Dr. Jansen served as Senior Vice President at Wyeth Pharmaceuticals and on Wyeth’s Research and Development Executive Committee since 2006 and was responsible for vaccine discovery, early development and clinical testing operations. Dr. Jansen also briefly worked at Vaxgen as Chief Scientific Officer and Senior Vice President for Research and Development with responsibility for the company’s late stage development programs.

Prior to joining Vaxgen, Dr. Jansen spent 12 years at Merck Research Laboratories where she directed or supported a number of vaccine efforts, including Merck’s novel bacterial vaccine programs and viral vaccine programs (rotavirus, zoster and mumps, measles and rubella). Dr. Jansen initiated and led the development of Gardasil®, the world’s first cervical cancer vaccine.


How does the Oxford & AstraZeneca COVID-19 vaccine work? A guide to viral vector vaccines

Relatively hot on the heels of the Pfizer & BioNTech RNA vaccine, today the UK has approved the Oxford University & AstraZeneca COVID-19 vaccine. The Oxford vaccine is a viral vector vaccine, which works slightly differently to the RNA vaccines. This graphic, made with the Royal Society of Chemistry, looks at how they work and highlights other vaccines of this type in use or development for COVID-19.

Some of the groundwork necessary to produce these vaccines is similar to that for the RNA vaccines we examined previously. As with those vaccines, we need to know the genetic code for the virus first. In particular, we need to know the code for virus proteins. Like the RNA vaccines, the viral vector vaccines make use of the code for the virus spike protein. This is the protein the virus uses to penetrate cells and kick off an infection.

RNA vaccines deliver the RNA directly to our cells, encapsulated in tiny fat droplets to protect it. The challenge with this approach has been well-documented: the vaccine must be stored at low temperatures to keep the RNA stable. This may make it harder to distribute and use these vaccines in some countries.

The viral vector vaccines get around this problem by smuggling the virus protein RNA into our cells in a different way. Scientists can add the RNA to the genetic material of another virus, a viral vector, which is then used in the vaccine.

As with the RNA vaccines, once the virus protein RNA is in our cells, our cellular machinery uses it as a blueprint to make the virus protein. This then causes an immune response, which trains our body’s immune system to recognise the SARS-CoV-2 virus. If we’re subsequently infected, our immune system will realise it’s seen part of this virus before, and marshall our immune response more quickly.

You might worry about the idea of smuggling in the SARS-CoV-2 virus RNA inside another virus. Isn’t there a risk that these viral vectors could themselves cause an infection? To avoid this risk, scientists use genetically altered viral vectors which can’t cause disease. The RNA which produces the SARS-CoV-2 spike protein is also broken down once our cells have made the protein, so this, too, poses no infection risk.

Vaccines can use several different viruses as viral vectors, but the most common amongst the COVID-19 vaccine candidates are adenoviruses. Adenoviruses are amongst the selection of viruses which can cause the common cold. It’s estimated that they cause a little under 5% of these infections.

Some of the COVID-19 vaccine candidates use human adenovirus viral vectors. This includes the Russian Sputnik V vaccine and the Chinese CanSino Biologics vaccine. One potential issue with these vectors is that, inevitably, some of us will have been exposed to these viruses before. Because of this, we may have some degree of immunity to them. This means the viral vector itself produces an immune response, which may mean that the immune response to the SARS-CoV-2 virus isn’t boosted as effectively.

The Oxford vaccine avoids these issues by using a chimp adenovirus instead. Far fewer people will have an existing immune response to the chimp adenovirus, so we can be confident that it won’t impact our immune response to the vaccine. Another vaccine in development in Italy has used a similar approach with a gorilla adenovirus.

All the viral vector vaccine candidates for COVID-19 are non-replicating. This means that they don’t create additional viral vectors in the cells that they infect. Though they need higher doses than replicating viral vector vaccines, it also adds to our confidence in their safety.

So if you get given the Oxford vaccine, what can you expect? Well, we know that viral vector vaccines cause a strong immune response. This can mean that the minor side effects of headaches and fever after taking the vaccine may be more common. But this is a positive sign that the vaccine is working, so isn’t a cause for concern.

The Oxford vaccine’s approval is undoubtedly good news. It’s important to remember, though, that the vaccination programme will take time. It’s not a “get out of jail free” card for the current wave of COVID-19 cases, and the weeks and months ahead will still be incredibly challenging, but it will hopefully help blunt COVID’s threat later in 2021.

This graphic was developed in partnership with the Royal Society of Chemistry.


A nanomaterial path forward for COVID-19 vaccine development

From mRNA vaccines entering clinical trials, to peptide-based vaccines and using molecular farming to scale vaccine production, the COVID-19 pandemic is pushing new and emerging nanotechnologies into the frontlines and the headlines.

Nanoengineers at UC San Diego detail the current approaches to COVID-19 vaccine development, and highlight how nanotechnology has enabled these advances, in a review article in Nature Nanotechnology published July 15.

"Nanotechnology plays a major role in vaccine design," the researchers, led by UC San Diego Nanoengineering Professor Nicole Steinmetz, wrote. Steinmetz is also the founding director of UC San Diego's Center for Nano ImmunoEngineering. "Nanomaterials are ideal for delivery of antigens, serving as adjuvant platforms, and mimicking viral structures. The first candidates launched into clinical trials are based on novel nanotechnologies and are poised to make an impact."

Steinmetz is leading a National Science Foundation-funded effort to develop -- using a plant virus -- a stable, easy to manufacture COVID-19 vaccine patch that can be shipped around the world and painlessly self-administered by patients. Both the vaccine itself and the microneedle patch delivery platform rely on nanotechnology. This vaccine falls into the peptide-based approach described below.

"From a vaccine technology development point of view, this is an exciting time and novel technologies and approaches are poised to make a clinical impact for the first time. For example, to date, no mRNA vaccine has been clinically approved, yet Moderna's mRNA vaccine technology for COVID-19 is making headways and was the first vaccine to enter clinical testing in the US."

As of June 1, there are 157 COVID-19 vaccine candidates in development, with 12 in clinical trials.

"There are many nanotechnology platform technologies put toward applications against SARS-CoV-2 while highly promising, many of these however may be several years away from deployment and therefore may not make an impact on the SARS-CoV-2 pandemic," Steinmetz wrote. "Nevertheless, as devastating as COVID-19 is, it may serve as an impetus for the scientific community, funding bodies, and stakeholders to put more focused efforts toward development of platform technologies to prepare nations for readiness for future pandemics," Steinmetz wrote.

To mitigate some of the downsides of contemporary vaccines -- namely live-attenuated or inactivated strains of the virus itself -- advances in nanotechnology have enabled several types of next-generation vaccines, including:

Peptide-based vaccines: Using a combination of informatics and immunological investigation of antibodies and patient sera, various B- and T-cell epitopes of the SARS-CoV-2 S protein have been identified. As time passes and serum from convalescent COVID-19 patients are screened for neutralizing antibodies, experimentally-derived peptide epitopes will confirm useful epitope regions and lead to more optimal antigens in second-generation SARS-CoV-2 peptide-vaccines. The National Institutes of Health recently funded La Jolla Institute for Immunology in this endeavor.

Peptide-based approaches represent the simplest form of vaccines that are easily designed, readily validated and rapidly manufactured. Peptide-based vaccines can be formulated as peptides plus adjuvant mixtures or peptides can be delivered by an appropriate nanocarrier or be encoded by nucleic acid vaccine formulations. Several peptide-based vaccines as well as peptide-nanoparticle conjugates are in clinical testing and development targeting chronic diseases and cancer, and OncoGen and University of Cambridge/DIOSynVax are using immunoinformatics-derived peptide sequences of S protein in their COVID-19 vaccine formulations.

An intriguing class of nanotechnology for peptide vaccines is virus like particles (VLPs) from bacteriophages and plant viruses. While non-infectious toward mammals, these VLPs mimic the molecular patterns associated with pathogens, making them highly visible to the immune system. This allows the VLPs to serve not only as the delivery platform but also as adjuvant. VLPs enhance the uptake of viral antigens by antigen-presenting cells, and they provide the additional immune-stimulus leading to activation and amplification of the ensuing immune response. Steinmetz and Professor Jon Pokorski received an NSF Rapid Research Response grant to develop a peptide-based COVID-19 vaccine from a plant virus. Their approach uses the Cowpea mosaic virus that infects legumes, engineering it to look like SARS-CoV-2, and weaving antigen peptides onto its surface, which will stimulate an immune response.

Their approach, as well as other plant-based expression systems, can be easily scaled up using molecular farming. In molecular farming, each plant is a bioreactor. The more plants are grown, the more vaccine is made. The speed and scalability of the platform was recently demonstrated by Medicago manufacturing 10 million doses of influenza vaccine within one month. In the 2014 Ebola epidemic, patients were treated with ZMapp, an antibody cocktail manufactured through molecular farming. Molecular farming has low manufacturing costs, and is safer since human pathogens cannot replicate in plant cells.

Nucleic-acid based vaccines: For fast emerging viral infections and pandemics such as COVID-19, rapid development and large scale deployment of vaccines is a critical need that may not be fulfilled by subunit vaccines. Delivering the genetic code for in situ production of viral proteins is a promising alternative to conventional vaccine approaches. Both DNA vaccines and mRNA vaccines fall under this category and are being pursued in the context of the COVID-19 pandemic.

  • DNA vaccines are made up of small, circular pieces of bacterial plasmids which are engineered to target nuclear machinery and produce S protein of SARS-CoV-2 downstream.
  • mRNA vaccines on the other hand, are based on designer-mRNA delivered into the cytoplasm where the host cell machinery then translates the gene into a protein -- in this case the full-length S protein of SARS-CoV-2. mRNA vaccines can be produced through in vitro transcription, which precludes the need for cells and their associated regulatory hurdles

While DNA vaccines offer higher stability over mRNA vaccines, the mRNA is non-integrating and therefore poses no risk of insertional mutagenesis. Additionally, the half-life, stability and immunogenicity of mRNA can be tuned through established modifications.

Several COVID-19 vaccines using DNA or RNA are undergoing development: Inovio Pharmaceuticals has a Phase I clinical trial underway, and Entos Pharmeuticals is on track for a Phase I clinical trial using DNA. Moderna's mRNA-based technology was the fastest to Phase I clinical trial in the US, which began on March 16th, and BioNTech-Pfizer recently announced regulatory approval in Germany for Phase 1/2 clinical trials to test four lead mRNA candidates.

Subunit vaccines: Subunit vaccines use only minimal structural elements of the pathogenic virus that prime protective immunity -- either proteins of the virus itself or assembled VLPs. Subunit vaccines can also use non-infectious VLPs derived from the pathogen itself as the antigen. These VLPs are devoid of genetic material and retain some or all of the structural proteins of the pathogen, thus mimicking the immunogenic topological features of the infectious virus, and can be produced via recombinant expression and scalable through fermentation or molecular farming. The frontrunners among developers are Novavax who initiated a Phase I/II trial on May 25, 2020. Also Sanofi Pasteur/GSK, Vaxine, Johnson & Johnson and the University of Pittsburgh have announced that they expect to begin Phase I clinical trials within the next few months. Others including Clover Biopharmaceuticals and the University of Queensland, Australia are independently developing subunit vaccines engineered to present the prefusion trimer confirmation of S protein using the molecular clamp technology and the Trimer-tag technology, respectively.

Delivery device development

Lastly, the researchers note that nanotechnology's impact on COVID-19 vaccine development does not end with the vaccine itself, but extends through development of devices and platforms to administer the vaccine. This has historically been complicated by live attenuated and inactivated vaccines requiring constant refrigeration, as well as insufficient health care professionals where the vaccines are needed. "Recently, modern alternatives to such distribution and access challenges have come to light, such as single-dose slow release implants and microneedle-based patches which could reduce reliance on the cold chain and ensure vaccination even in situations where qualified health care professionals are rare or in high demand," the researchers write. "Microneedle-based patches could even be self-administered which would dramatically hasten roll-out and dissemination of such vaccines as well as reducing the burden on the healthcare system."

Pokorski and Steinmetz are co-developing a microneedle delivery platform with their plant virus COVID-19 vaccine for both of these reasons.

This work is supported by a grant from the National Science Foundation (NSF CMMI-2027668)

"Advances in bio/nanotechnology and advanced nanomanufacturing coupled with open reporting and data sharing lay the foundation for rapid development of innovative vaccine technologies to make an impact during the COVID-19 pandemic," the researchers wrote. "Several of these platform technologies may serve as plug-and-play technologies that can be tailored to seasonal or new strains of coronaviruses. COVID-19 harbors the potential to become a seasonal disease, underscoring the need for continued investment in coronavirus vaccines."