VACCINATION: COVID-19 special- Dr Srikant Sharma

The vaccine development progresses through pre-clinical evaluation and distinct clinical stages, phases I, II,III. Traditionally, these steps occur sequentially, and each usually takes several years for completion.

Initially, early vaccine candidates are administered to small animals, often mice, and the resulting immune responses are measured. The vaccine must generate an immune response to undergo further testing. Toxicity studies are also conducted in animals to detect any safety concerns.

It enrolls healthy subjects, usually fewer than 100 individuals, generally between the ages of 18 to 55 years. The primary objective is to test the safety of the experimental vaccine, although immunogenicity is also measured. Phase I studies also often involve dose-ranging studies, so that the first enrolled subjects are administered the lowest doses of vaccine and, if tolerated, the doses are increased in subsequent subjects.

It is done to check the efficacy of the vaccine, to decrease it to the lowest optimal dose to develop an immune response. It is usually done in several hundred individuals.

Phase III trials are large-scale clinical trials enrolling thousands of subjects from the target population. They are conducted in "field" conditions that are similar to future routine use. It is a multi centric study done in various centers across the world.

If the phase III results demonstrate efficacy and safety, the manufacturer of the vaccine can submit an application to the national regulatory authority to license and market the product.

Vaccine efficacy in percent is the reduction in specific disease incidence among those who received vaccine versus those who received the control product and is assessed by the following formula:

Attack rate in the unvaccinated –

● attack rate in the vaccinated/attack rate in the unvaccinated) x 100.

The major antigenic target for both SARS-CoV-1 and MERS vaccines was the large surface spike protein. An analogous protein is also present in SARS-CoV-2; it binds to the angiotensin-converting enzyme 2 (ACE2) receptor on host cells and induces membrane fusion .

Based on data from SARS-CoV-1 and MERS-CoV vaccine studies, as well as observations that antibodies binding to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein can prevent attachment to the host cell and neutralize the virus, the spike protein became the predominant antigenic target for SARS-CoV-2 vaccine development.

All the vaccines which are under development like DNA, RNA, Vector based vaccine ultimately translate into glycoproteins and the body produces antibodies against these glycoproteins.

The site of vaccine delivery may impact the character of the immune response. Natural respiratory infections elicit both mucosal and systemic immune responses. Most vaccines, however, are administered intramuscularly (or intradermally) and elicit primarily a systemic immune response, with less robust protection in the upper respiratory mucosa than after natural infection.

According to WHO, as of November 12th 2020, there are 48 vaccines in Clinical Trials and 164 candidate vaccines in Pre-clinical evaluations. Following are a few examples along with various vaccine platforms under development.

1. DNA Vaccines (eg. Inovio)

2. RNA Vaccine (eg. Moderna, Pfizer)

3. Viral Vector (eg. Oxford/AstraZeneca, Janssen,Gamalaya-Sputnik)

4. Viral protein Subunit (eg. Novavax, AdaptVac, Clover Biopharma)

5. Live Attenuated (eg. Codagenix, Indian Immunologicals Ltd.)

6. Inactivated Virus (eg. SinoVac, SinoPharm, Bharat Biotech)

Live attenuated vaccines are produced by developing genetically weakened versions of the wild-type virus; these weakened viruses replicate in the recipient to generate an immune response but do not cause disease. Attenuation can be achieved by modifying the virus genetically or by growing it in adverse conditions so that virulence is lost but immunogenicity is maintained.

● It has the intrinsic ability to stimulate the immune system by inducing the toll-like receptors (TLRs) namely: TLR 3, TLR 7/8, and TLR 9 of the innate immune system that involves B cells, CD4 and CD8 T cells.

● It can be derived from 'cold adapted' virus strains, reassortants, and reverse genetics.

● LAV requires extensive accessory testing to establish safety and efficacy.

● There is a probability of nucleotide substitution during viral replication, resulting in the creation of recombinants post vaccination.

Inactivated vaccines are produced by growing SARS-CoV-2 in cell culture then chemically inactivating the virus . The inactivated virus is often combined with alum or another adjuvant in the vaccine to stimulate an immune response. Inactivated vaccines are typically administered intramuscularly. They require a biosafety level 3 facility for production.

● Stable and safer as compared to the LAVs.

● It has the pre-existing technology and infrastructure required for its development.

● Has already been tested for SARS-CoV and various other diseases.

● It can be used along with adjuvants to increase their immunogenicity.

Require the booster shots to maintain the immunity.

● Furthermore, large amounts of viruses need to be handled and the integrity of the immunogenic particles must be maintained.

Recombinant protein vaccines are composed of viral proteins that have been expressed in one of various systems, including insect and mammalian cells, yeast cells, and plants. They do not require replication of the live virus (which facilitates production). Although production yields depend on the ability to express the spike protein. Recombinant SARS-CoV-2 vaccines in development include recombinant spike protein vaccines, recombinant RBD vaccines, and virus-like particle (VLP) vaccines

Do not have any live component of the viral particle. Thus, it is safe with fewer side-effects

Induce an immune response BUT Memory for future responses is doubtful

Replication-incompetent vector vaccines use a different vector virus that has been engineered to not replicate in vivo and to express the viral protein that is the intended immune target. Many replication-incompetent vector vaccine candidates use adenovirus vectors, but other vectors include modified vaccinia Ankara (MVA), human parainfluenza virus, influenza virus, adeno-associated virus (AAV), and Sendai virus .

● Show a highly specific gene delivery into the host cell with a vigorous immune response.

● Avoids handling of any infectious particle and it has been used widely for MERS-CoV with positive results from the trials

● The host may possess immunity against the vector due to prior exposure, reducing the efficacy.

● May lead to cancer due to the integration of the viral genome into the host genome

DNA vaccines consist of plasmid DNA that contain mammalian expression promoters and the target gene, so that the target protein is expressed in the vaccine recipient. Large quantities of stable plasmid DNA can be generated in Escherichia coli, which is a major production advantage.

The synthetic DNA is temperature stable and cold-chain free

● It can be developed at an accelerated pace.

● It does not require the handling of the infectious viral particle.

Though it elicits both Cytotoxic and humoral immunity, the titers remain low.

● Insertion of foreign DNA into the host genome may cause abnormalities in the cell.

● May induce the antibody production against itself.

RNA vaccines were the first vaccines for SARS-CoV-2 to be produced and represent an entirely new vaccine approach. Once administered, the RNA is translated into the target protein, which is intended to elicit an immune response. The mRNA remains in the cell cytoplasm and does not enter into the nucleus; mRNA vaccines do not interact with or integrate into the recipient's DNA. These vaccines are produced completely in vitro, which facilitates production.

● The translation of mRNA occurs in the cytosol of the host cell averting the risk of any sort of integration into the host genome.

● Safety issues with reactogenicity have been reported for various RNA based vaccines.

● It also shows instability.

A. mRNA vaccines

1. BNT162b2 (BioNTech and Pfizer)

2. mRNA 1273 (Moderna)

B. Vector based vaccine

3. ChAdOx1 nCoV-19/AZD1222/ Covishield (University of Oxford, AstraZeneca, and the Serum Institute of India)

4. Ad26.COV2.S (Janssen)

5. Ad5-based COVID-19 vaccine (CanSino Biologics)

6. Sputnik V (Gamaleya Institute)

C. Inactivated vaccine

7. BBIBP-CorV (Sinopharm)

8. CoronaVac (Sinovac)

9. Bharat Biotech's Covaxin

D. Protein subunits

10. Sanofi vaccines

11. NVX-CoV2373 (NOVOVAX)

It is an mRNA vaccine that is delivered in a lipid nanoparticle to express a full-length spike protein. It is given intramuscularly in two doses 21 days apart. BNT162b2 has been authorized for use in the United States, United Kingdom (UK), and Canada. Local and systemic adverse effects were dose dependent and relatively common after the second dose. Among participants younger than 55 years,-fever occurred in 16 % , moderate to severe fatigue in 38% population , Headache in 26% and Chills in 18%. Indications-individuals age 16 years or older Individuals with a history of SARS-CoV-2 infection should still receive the vaccine, if indicated; pre-vaccination serologic screening is not recommended. It is reasonable for individuals with recent, documented SARS-CoV-2 infection to delay vaccination for 90 days from the time of infection to allow others to receive vaccine sooner, as the risk of reinfection appears extremely low during this interval.Contraindications - in individuals with a history of severe allergic reaction to any component of the vaccine

2. mRNA 1273 (Moderna)

messenger RNA (mRNA) vaccine was one of the first vaccines for SARS-CoV-2 to be produced. It was developed and administered to humans within two months of publication of the SARS-CoV-2 genomic sequence.This vaccine utilizes mRNA delivered in a lipid nanoparticle to express a full-length spike protein. It is given intramuscularly in two doses 28 days apart. CD4 cell responses with a TH1 bias what also detected. Vaccination in older adults more than 55 years of age also elicited immune responses that were comparable to those seen in the younger population. Binding and neutralising antibody responses declined slightly over three months in participants from all age groups but remained elevated compared with levels seen in convalescent plasma. Local and systemic reactions were common particularly after the second dose.

1. NO trials done in India, have directly applied for emergency authorization.

2. Vaccine will arrive at a temperature between -80°C and 60°C (-112°F to -76°F) in a thermal shipping container with dry ice.

3. no supply commitment is a major drawback

4. Storage and transportation of vaccines in an ultra-cold freezer, thermal shipping container, or refrigerator is difficult in tropical countries like India.

It is based on a replication-incompetent chimpanzee adenovirus vector that expresses the spike protein.It is given intramuscularly and is being evaluated as a single dose or two doses 28 days apart. In a single-blind, randomized controlled phase I/II trial in healthy individuals 18 to 55 years old, in which most of the vaccine recipients received a single dose and a small cohort received an additional booster dose, neutralizing antibody titers 28 days after the last dose were comparable to those detected in convalescent plasma.

The levels of antibody titers achieved were higher following two doses; and subsequent studies are evaluating the two-dose regimen. Cellular immune responses were also detected. Vaccine efficacy was 90.0 percent (95% CI 28.0-78.2) among the 2741 participants who received the lower dose and 62.1 percent (95% CI 41-75.7) among those who received full-dose vaccine.Reasons for this difference are uncertain, although the overlapping confidence intervals indicate that the difference is not statistically significant. In the phase III trial, there were two cases of transverse myelitis in ChAdOx1 nCoV-19 vaccine recipients.

Serum institute of india has applied for emergency authorization.Serum Institute of India (SII) is likely to submit the final COVID-19 vaccine trial data before the end of December.

It is India's first vaccine against COVID-19.

It is an inactivated whole SARS-CoV-2 virus vaccine developed by Bharat BioTech, Indian Council of Medical Research (ICMR) and National Institute of Virology (NIV). It has successfully cleared Phase I/II human trials and is given permission for Phase III trial by DCGI (Drug Controller General of India).

The vaccine trial Phase I/II has been conducted in 12 hospitals in different cities across the country, in healthy volunteers with no comorbid conditions.

The vaccine was found to generate robust immune responses, thereby preventing infection and disease in the primates upon high amount of exposure to live SARS-CoV-2 virus.As per the vaccine makers the phase III study would cover around 28,500 subjects aged 18 years and above, however the complete safety and immunogenicity data of the phase II trial is still not revealed.

Two potential vaccine candidates by Sanofi.

The first candidate is a recombinant protein-adjuvanted vaccine, developed in partnership with GSK.

The initial results from a phase 1/2 clinical trial showed an immune response comparable to patients who recovered from COVID-19 in adults aged 18 to 49 years, but a low immune response in older adults likely due to an insufficient concentration of the antigen.

The second vaccine candidate uses novel messenger RNA technology, and is being developed in partnership with Translate Bio. The project is on track to start phase 1/2 clinical trials in early 2021, with earliest potential approval in the second half of the year.

It is based on a replication-incompetent adenovirus 26 vector that expresses a stabilized spike protein. It is given intramuscularly and is being evaluated as a single dose.

In a report from a phase I/II randomized, double-blind, placebo controlled trial described high rates of neutralising and binding antibodies after a single vaccine dose in healthy individuals 18 to 85 years old; these responses overlapped with but were slightly lower than those in convalescent plasma . CD4 cell responses with a Th1 bias were also detected.

It is based on a replication-incompetent adenovirus 5 vector that expresses the spike protein. It is given as a single intramuscular dose. In early clinical trials, it was immunogenic in healthy adults at 28 days with only mild to moderate local and systemic reactions. This vaccine has been licensed in China for limited use by the military.

It was developed in Russia that uses two replication-incompetent adenovirus vectors that express a full-length spike glycoprotein.

The vaccine is given intramuscularly as an initial adenovirus 26 vector dose followed by an adenovirus 5 vector boosting dose 28 days later. The vaccine was associated with mild to moderate local and systemic reactions, but SARS-CoV-2 humoral and cellular immune responses were detected in the participants.

Russian officials reported a 91.4 percent efficacy rate following interim analysis of a phase III trial; however, the validity of this estimate is questionable because it is based on only 39 cases.

It is a recombinant protein nanoparticle vaccine composed of primary spike like glycoprotein and a potent Matrix M1 adjuvant. It is given intramuscularly in two doses 21 days apart. The adjuvant vaccine induces high binding and neutralising responses, comparable to those in convalescent plasma from patients who have been recovered with COVID-19.CD4 cell responses with a TH1 bias were also detected.

Approximately 6% of the participants experienced systematic effects mainly fatigue, headache, myalgia and or malaise following the second dose.

It is an inactivated vaccine based on a SARS-CoV-2 isolate from a patient in China. It has an aluminum hydroxide adjuvant. It is given intramuscularly in two doses 28 days apart.

In phase I/II placebo-controlled randomized trials of healthy individuals 18 to 80 years old, all recipients of two vaccine doses developed neutralizing and binding antibodies; no severe reactions were reported.

It is an inactivated SARS-CoV-2 vaccine which was developed in China. It has an aluminum hydroxide adjuvant.It is given intramuscularly in two doses 28 days apart.

A variety of COVID-19 vaccines are being developed around the world.

All of them share one thing in common: they all stimulate a primary immune response so that the body can develop memory B and T cells against the SARS-CoV-2 virus. The development of immune memory by vaccines is what will protect the person against subsequent COVID-19 infection.

Each COVID-19 vaccine has distinct advantages and disadvantages, but the development of different COVID-19 vaccines provides some redundancy and overlap. In case a vaccine is unsafe in humans or fails to protect people against COVID-19, the world has other COVID-19 vaccines that it can trial and produce. It is this pursuit of multiple vaccines that will allow the global population to be immunised sooner, allowing COVID-19 to be eliminated so that the world can start to recover from the pandemic!!

YES.

Although preference of vaccination should be given to those who are not yet infected with COVID-19.

Only if vaccines are developed on egg culture media, it should not be given in people with egg allergies.

All are almost equally efficacious. Earliest is better. Currently looking at the scenario, the only earliest vaccine expected is ChAdOx1 nCoV-19/AZD1222 named as COVISHIELD being developed by serum institute of India.

Until now the studies show efficacy upto 3-6 months, although literature says efficacy can be there upto a year or even 3 years.

The body generates a primary immune response when exposed to the SARS-CoV-2 virus for the first time or gets the 1st dose of the vaccine. The primary immune response is slow and weak as it takes days for the body to generate enough antibodies and T cells to eliminate the virus.

However, the body generates long-lasting memory B and T cells that "remember" the SARS-CoV-2 virus, generating immune memory. When the virus enters the body for the second time or the 2nd dose of the vaccine is given, the body develops a secondary immune response.

The secondary immune response is stronger and quicker than the primary immune response as memory B and T cells are rapidly activated. This results in higher antibody concentrations and T cell counts around the body to eliminate the virus more quickly, reducing the symptoms and severity of COVID-19.

In addition, more memory B and T cells are produced after infection which strengthens memory of the SARS-CoV-2 virus.

Only live attenuated vaccines cannot be given in immunocompromised individuals. Rest vaccines are safe as they don't involve any live viral component.

Unlike the other vaccines which are given in children first, COVID-19 vaccine is to be given in adults first because it is seen that in children the disease is less severe and is not causing mortality. The study has only been done in adults as of yet, and children study to follow.

Though chances of hospitalization, or getting severe virus infection is eliminated after vaccination. But individuals still have a small percentage of chance to secrete little virus in mucous, cough, running nose and expectoration.

YES, As we still don't know the rate of antibodies production; and the possibility of spread of a smaller percentage of virus (as explained in above-mentioned answer) : masks are mandatory even after getting vaccinated.

If the vector is dead vector i.e replication incompetent it cannot spread any diseases even in immunocompromised individual.

The impact of COVID-19 vaccines on the pandemic will depend on several factors. These include factors such as the effectiveness of the vaccines; how quickly they are approved, manufactured, and delivered; and how many people get vaccinated.

Most scientists anticipate that, like most other vaccines, COVID-19 vaccines will not be 100% effective. However we are looking forward for the vaccines to come, so that at least the mortality is reduced and the transmission is paused if not completely stopped.

Vaccines produce antibodies against many regions in the spike protein, so it's unlikely that a single change would make the vaccine less effective. However in upcoming times as the mutations occur the vaccine may need to be altered.

Though the vaccines may take years to develop, due to ongoing world pandemic time will tell about the safety and efficacy of vaccines and how soon will we have a normal life back, or will this be the 'new normal'!