Thursday, May 7, 2020



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.


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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