CMAAO CORONA FACTS and MYTH BUSTER 87 Vaccine
Dr K K
Aggarwal
President
Confederation of Medical Associations of Asia and Oceania, HCFI, Past National
President IMA, Chief Editor Medtalks
With inputs from Dr Monica Vasudeva
808: Coronavirus vaccine research
Coronaviruses have a spike-like structure on their
surface called an S protein. (The spikes create the corona-like, or crown-like,
appearance that gives the viruses their name.) The S protein attaches to the
surface of human cells. A vaccine that targets this protein would prevent it
from binding to human cells and stop the virus from reproducing.
809: Coronavirus vaccine challenges
Past research on vaccines for coronaviruses has also
identified some challenges to developing a COVID-19 vaccine, including:
Ensuring vaccine safety. Several vaccines for SARS
have been tested in animals. Most of the vaccines improved the animals'
survival but didn't prevent infection. Some vaccines also caused complications,
such as lung damage. A COVID-19 vaccine will need to be thoroughly tested to
make sure it's safe for humans.
Providing long-term protection. After infection with
coronaviruses, re-infection with the same virus — though usually mild and only
happening in a fraction of people — is possible after a period of months or
years. An effective COVID-19 vaccine will need to provide people with long-term
infection protection.
Protecting older people. People older than age 50 are
at higher risk of severe COVID-19. But older people usually don't respond to
vaccines as well as younger people. An ideal COVID-19 vaccine would work well
for this age group.
Pathways to
develop and produce a COVID-19 vaccine
810: Live
vaccines
Live vaccines use a weakened (attenuated) form of the
germ that causes a disease. This kind of vaccine prompts an immune response
without causing disease. The term attenuated means that the vaccine's ability
to cause disease has been reduced.
The starting
point for a live vaccine is a virus that is known, but harmless. It does not
cause disease, but is able to multiply within the cells of our bodies. This is
the vector which then triggers an immune response.
Live vaccines are used to protect against measles,
mumps, rubella, smallpox and chickenpox. As a result, the infrastructure is
in place to develop these kinds of vaccines. However, live virus vaccines often
need extensive safety testing. Some live viruses can be transmitted to a person
who isn't immunized. This is a concern for people who have weakened immune
systems.
811: Inactivated vaccines
Inactivated vaccines use a killed (inactive) version
of the germ that causes a disease. This kind of vaccine causes an immune
response but not infection. Inactivated vaccines are used to prevent the
flu, polio, hepatitis A, B, tetanus, whooping cough and rabies.
The dead viruses can no longer multiply, but the body
still recognizes them as intruders, so the body's defense system ensures that
antibodies are produced. The vaccinated individual does not develop the
disease.
However, inactivated vaccines may not provide
protection that's as strong as that produced by live vaccines. This type of
vaccine often requires multiple doses, followed by booster doses, to provide
long-term immunity. Producing these types of vaccines might require the
handling of large amounts of the infectious virus.
812: Genetically engineered vaccines
This type of vaccine uses genetically engineered RNA
or DNA that has instructions for making copies of the S protein. These copies
prompt an immune response to the virus. With this approach, no infectious virus
needs to be handled. While genetically engineered vaccines are in the works, none
has been licensed for human use.
813: The vaccine development timeline
The development of vaccines can take years. This is
especially true when the vaccines involve new technologies that haven't been
tested for safety or adapted to allow for mass production.
814: Why does it take so long?
First, a vaccine is tested in animals to see if it
works and if it's safe. This testing must follow strict lab guidelines and
generally takes three to six months. The manufacturing of vaccines also must
follow quality and safety practices.
Next comes testing in humans. Small phase I clinical
trials evaluate the safety of the vaccine in humans. During phase II, the
formulation and doses of the vaccine are established to prove the vaccine's
effectiveness. Finally, during phase III, the safety and efficacy of a vaccine
need to be demonstrated in a larger group of people.
It's unlikely that a COVID-19 vaccine will become
available sooner than six months after clinical trials start. Realistically, a
vaccine will take 12 to 18 months or longer to develop and test in human
clinical trials. And we don't know yet whether an effective vaccine is possible
for this virus.
If a vaccine is approved, it will take time to
produce, distribute and administer to the global population. Because people
have no immunity to COVID-19, it's likely that two vaccinations will be needed,
three to four weeks apart. People would likely start to achieve immunity to
COVID-19 one to two weeks after the second vaccination.
815: Monoclonal Antibodies ( 808)
The use of mAbs
directed against infectious pathogens is an area of investigation. The
mechanism is not completely defined. Potential uses include preventing or
treating specific infections.
Most mAbs target
proteins on the surface of a virus, thus neutralizing the virus from entering
cells. Palivizumab is an antibody against the respiratory syncytial virus (RSV)
fusion (F) glycoprotein; it inhibits viral entry into host cells. This is approved
by US FDA for the prevention of RSV infection. ('Immunoprophylaxis'.)
Other
investigational preventive antiviral mAbs include those targeting the conserved
hemagglutinin A stem of Haemophilus influenzae. This therapy may be helpful in
cases in which vaccination offers ineffective humoral immunity.
Investigational
mAbs against HIV can improve immunity during active infection, with promising results
in animal models using broadly neutralizing antibodies
Some mAbs against
bacteria can function both prophylactically and therapeutically (eg, by
targeting the protective antigen domain of Bacillus anthracis or one of the
Clostridioides [formerly Clostridium] difficile toxins).
As stated in 2018, mAbs
directed against pathogens are unlikely to be used routinely due to their high
cost and requirement for parenteral administration; however, they may be
especially useful for certain emerging infectious diseases.
Treatment of active
disease and/or targeted prophylaxis might be especially important in
individuals who have not been vaccinated against a pathogen but require
immediate protection (individuals infected with Ebola virus, pregnant women
residing in Zika virus-endemic areas and COVID 19).
816: Inactivated Coronavirus Vaccine
The immunogenicity
and efficacy of inactivated SARS-CoV vaccines have been established in
experimental animals, and one such vaccine is being evaluated in a clinical
trial. However, the development of inactivated vaccines requires the
propagation of high titers of infectious virus, which in the case of SARS-CoV
requires biosafety level 3-enhanced precautions and is a safety concern for
production. Additionally, incomplete inactivation of the vaccine virus presents
a potential public health threat. Production workers are at risk for infection
during handling of concentrated live SARS-CoV, incomplete virus inactivation
may cause SARS outbreaks among the vaccinated populations, and some viral
proteins may induce harmful immune or inflammatory responses, even causing
SARS-like diseases
817: Live
Attenuated Coronavirus Vaccine
To date, live
attenuated vaccines for SARS-CoV have not been evaluated. However, systems have
been developed to generate cDNAs encoding the genomes of CoVs, including
SARS-CoV. The panel of cDNAs spanning the entire CoV genome can be
systematically and directionally assembled by in vitro ligation into a
genome-length cDNA from which recombinant virus can be rescued. This system has
been used for genetic analysis of SARS-CoV protein functions and will enable
researchers to engineer specific attenuating mutations or modifications into
the genome of the virus to develop live attenuated vaccines. While live
attenuated vaccines targeting respiratory viruses, including influenza viruses
and adenoviruses, have been approved for use in humans, the observation that
infectious virus is shed in the feces of SARS-CoV-infected individuals raises
concerns that a live attenuated SARS-CoV vaccine strain may also be shed in
feces, with potential to spread to unvaccinated individuals. Another concern is
the risk of recombination of a live attenuated vaccine virus with wild-type
CoV; however, there may be ways to engineer the genome of the vaccine virus to
minimize this risk.
818: S
Protein-based Coronavirus Vaccine
The roles of S
protein in receptor binding and membrane fusion indicate that vaccines based on
the S protein could induce antibodies to block virus binding and fusion or
neutralize virus infection. Among all structural proteins of SARS-CoV, S
protein is the main antigenic component that is responsible for inducing host
immune responses, neutralizing antibodies and/or protective immunity against
virus infection. S protein has therefore been selected as an important target
for vaccine and anti-viral development.
Although
full-length S protein-based SARS vaccines can induce neutralizing antibody
responses against SARS-CoV infection, they may also induce harmful immune
responses that cause liver damage of the vaccinated animals or enhanced
infection after challenge with homologous SARS-CoV, raising concerns about the
safety and ultimate protective efficacy of vaccines that contain the
full-length SARS-CoV S protein.
819: Vectored
Vaccines against Coronavirus
Several groups have
reported preclinical evaluation of vaccines utilizing other viruses as vectors
for SARS-CoV proteins, including a chimeric parainfluenza virus, MVA, rabies
virus, vesicular stomatitis virus (VSV), and adenovirus. Chimeric bovine/human
parainfluenza virus 3 (BHPIV3), a live attenuated parainfluenza virus vaccine
candidate, was utilized as a vector for the SARS-CoV structural proteins
including S, N, matrix (M), and envelope (E), alone or in combination. Studies
with vectored vaccines further demonstrate that induction of S protein-specific
NAbs is sufficient to confer protection.
The way this
works is, for example, when vaccine developers use genetic engineering to
disguise these viruses as SARS-CoV-2 viruses by giving them a corresponding
surface protein. This is a particularly good approach when seeking to combat
new types of pathogen.
When a person is given the vaccine,
their body builds up immunity. This protection then enables it to ward off
actual infection by the disease. A vector vaccine of this kind was used against
smallpox, and the first approved Ebola vaccine is also based on a vector virus.
820: DNA Vaccines
against Coronavirus
DNA vaccines have
demonstrated strong induction of immune responses to viral pathogens in animal
models, specifically in mice; however, clinical data on DNA vaccines in human
subjects are limited. DNA vaccines encoding the S, N, M, and E proteins of
SARS-CoV have been evaluated in mice. Vaccination with S-, M-, and N-encoding
DNA vaccines induced both humoral and cellular immune responses, with some
variation in the relative levels of induction.
821: Combination
Vaccines against Coronavirus
Combination
vaccines have also been evaluated for their ability to augment immune responses
to SARS-CoV. Administration of two doses of a DNA vaccine encoding the S
protein, followed by immunization with inactivated whole virus, was shown to be
more immunogenic in mice than either vaccine type alone. The combination
vaccine induced both high humoral and cell-mediated immune responses. High NAb
titers were also observed in mice vaccinated with a combination of S DNA
vaccines and S peptide generated in Escherichia coli. Combination vaccines may
enhance the efficacy of DNA vaccine candidates.
The SARS-CoV
vaccine strategies reported to date demonstrate that S protein-specific NAbs
alone are sufficient to provide protection against viral challenge. While
SARS-CoV has not yet reemerged, its unknown reservoir leaves open the
possibility that it, or a related virus, will again infect the human
population. The development of vaccines targeting this virus will help, in the
event of its reemergence, to potentially stop its spread before it wreaks the
social and economic havoc caused by the previous outbreak. Furthermore, lessons
learned from the generation of these vaccines may aid in the development of
future vaccines against known and newly identified coronaviruses.
822: The gene-based vaccines
Contain pure
genetic information in the form of coronavirus DNA or mRNA. Individual parts of
genetic information from the pathogen are packed into nanoparticles and
introduced into cells. Once the vaccine is in the body, it should form harmless
viral proteins that build up immune protection. So far, though, no such vaccine
exists on the market. They are still in development, with various companies and
institutes conducting research into them. The first vaccine to have received
Phase I approval in Germany is an mRNA vaccine.
Summary
1.
Virus vaccines (Live attenuated or inactivated): At least seven
teams are developing vaccines using the virus itself, in a weakened or
inactivated form. Many existing vaccines are made in this way, such as those
against measles and polio, but they require extensive safety testing. Sinovac
Biotech in Beijing has started to test an inactivated version of SARS-CoV-2 in
humans.
2.
Viral-vector vaccines ( Replicating
or non replicating) : Around
25 groups say they are working on viral-vector vaccines. A virus such as measles
or adenovirus is genetically engineered so that it can produce coronavirus
proteins in the body. These viruses are weakened so they cannot cause disease.
There are two types: those that can still replicate within cells and those that
cannot because key genes have been disabled.
3.
Nucleic-acid
vaccines: At least 20 teams
are aiming to use genetic instructions (in the form of DNA or RNA) for a
coronavirus protein that prompts an immune response. The nucleic acid is
inserted into human cells, which then churn out copies of the virus protein;
most of these vaccines encode the virus’s spike protein
4.
Protein-based
vaccines: Many researchers
want to inject coronavirus proteins directly into the body. Fragments of
proteins or protein shells that mimic the coronavirus’s outer coat can also be
used. ( virus subunit or virus like particle)
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