Clinical trial SARS-CoV2 candidate vaccines

Mitigating the anticipated emergence of 3rd spike
Clinical trial SARS-CoV2 candidate vaccines
A health worker administering a COVID-19 jab in Jammu. Mir Imran/ GK File

Wild-type (Wt) SARS-CoV2 that emerged from zoonotic transmission has to date claimed 3.89 million deaths worldwide (WHO, 2021). Presently, more than 8 variants of concern (VOC) are circulating in different countries and among them the Delta-plus variant has been studied to have a high transmission and infectivity. The emergence of SARS-CoV2−VOC is reflecting towards the selective-pressure build on Wt-SARS-CoV2 that consequently gave rise to quasi-species viral populations like Delta virus in vogue. Use of Remidesivir, IFNα, IFNβ, IFNγ, convalescent plasma, antibiotics, and persistent infection in the host-cells are some of the driving forces behind the emergence of VOCs. Progressive accumulation of the mutations in the SARS-CoV2-receptor-binding domain has led to the emergence of SARS-CoV2 variants, capable of evading from human immune response, convalescent plasma therapy, antiviral inhibitors, and may be from the presently available vaccines as well.

Vaccines

It is a biological agent that can be safely used to elicit an immune response ,thereby conferring protection against infection and/or disease on subsequent exposure to a pathogen (Nature Reviews | Immunology, 2021). Edward Jenner, “father of Immunology '' pioneered the concept of vaccine. The term vaccine and vaccination are derived from VariolaeVaccinae(smallpox of the cow). Vaccines exploit the ability of the highly evolved human immune system to respond to, and to memorize encounters with pathogen antigens.

Active and Passive Immunization

Passive Immunity: The agents used for inducing this immunity include preformed antibodies from humans or animals. Active Immunity: This is achieved by inoculating the humans and animals with attenuated microbial pathogens that induce immunity but do not cause any disease. Herd Immunity: When the whole population is immune to a particular disease.

The World Health Organization (WHO) estimates that 2–3 million lives are saved each year by current immunization programmes, contributing to the drastic reduction in paediatric mortality globally from 93 deaths/1000 live births in 1990 to 39 deaths/1000 live births in 2018. (www.who.int/gho/2020) Despite the advancement in the field of immunology, vaccines against hard-to-target pathogens like Mycobacterium tuberculosis, HIV, and recent SARS-CoV2 outbreaks. Therefore, we need to further understand how immune-system can be educated to eradicate such dreadful diseases.

CLASSIFICATION OF VACCINES

A. Recombinant Vaccines

Viral vectors, nucleic acid-based RNA and DNA vaccines, and virus-like particles SARS-CoV2 vaccines

B. Whole-Organism Vaccines:Inactivated (killed) bacterial cells or viral particles, Live but attenuated (avirulent) bacterial cells or viral particles

C. Purified Macromolecules as Vaccines: Bacterial Polysaccharide Capsules are used as Vaccines

Recombinant vaccines

Immunogenic protein can be cloned and expressed in bacterial, yeast, or mammalian cells using recombinant DNA technology.A number of genes encoding surface antigens from viral, bacterial, and protozoan pathogens have been successfully cloned into bacterial, yeast, insect, or mammalian expression systems, and the expressed antigens used for vaccine development. The first such recombinant antigen vaccine approved for human use was hepatitis B vaccine. This vaccine was developed by cloning the gene surface antigen of hepatitis B virus (HBsAg) in a yeast-expression system.

European Union Vaccine program for SARS-CoV2

According to WHO on January 5th, 2021, there are 63 candidate SARS CoV2 vaccines in human clinical trials and more than 172 candidates in preclinical stage. Among the 60 clinically evaluated vaccines, 13 leading candidate vaccines have already entered in Phase 3 clinical trials in an unprecedentedly expeditious vaccine development effort.

BharatBiotech, India, Pfizer and BioNTech, Sanofi-GSK,Sinopharm, AstraZeneca and the University of Oxford, Johnson & Johnson and Moderna, Sputnik V, Russian Direct Investment Fund, Russia are WHO-listed vaccines.

CURRENT VACCINES AGAINST SARS-COV2 IN PHASE-3 CLINICAL EVALUATION

Nucleic-acid vaccines

1. Boston-based Moderna vaccine: Therapeutics partnered up with the National Institute of Allergy and Infectious Diseases (NIAID) to produce the first vaccine candidate that entered clinical trials in 63 days after the genome sequencing of SARS-CoV-2. mRNA of SARS-CoV-2 Spike (S) protein encapsulated in a lipid nanoparticle vector that enhances uptake by the host cells. In preclinical studies, administration of mRNA-1273 induced potent humeral and cellular responses in BALB/cJ, C57BL/6J, and B6C3F1/J mice models that received two intramuscular doses of 1 μg mRNA-1273, 3-weeks apart. Apart from induction of high levels of virus-specific antibodies, administration of mRNA-1273 was found to elicit neutralizing antibodies against SARS-CoV2. Immunized mice also developed robust Th1-skewed CD4+ and CD8+ antigen-specific responses.

2. 100 μg of Moderna dose was found to be more immunogenic supporting its use in a Phase vaccine trial.

3. On December 30th, the safety and efficacy results from the Phase 3 trial of mRNA-1273 were published in the New England Journal of Medicine (NEJM), confirming the 94.1% efficacy and safety profile of this vaccine.

A. mRNA-BNT162b2/Comirnaty (Pfizer/BioNTech/FosunPharma)

1. The second candidate mRNA vaccine is BNT162b2 developed by Pfizer in collaboration with German based BioNTechand Shanghai-based FosunPharma. BioNTech initially developed and tested four modified mRNA-based (mod-RNA) vaccine candidates designed to be administered in two vaccinations 3-weeks apart. When these mRNA-based vaccines find its way in the host cell cytoplasm, it consequently instructs immune cells to make several copies of the full-length SARS-CoV-2 spike protein. Preliminary data in non-human primate models revealed that immunization of BALB/c mice with candidate BNT162b2 triggers strong humoral and cellular anti-SARS-CoV-2 responses characterized by high titers of anti-SARS-CoV-2 neutralizing antibodies coupled with the activation of CD8+ and CD4+ T lymphocytes, exhibiting a Th1 skewed phenotype.

2. A two-dose immunization with 30μg/dose of BNT162b1 was found to induce neutralizing anti-SARS-CoV-2 antibodies and virus-specific Th1 and CD8+ T cell responses.

3. Data suggest that mod-RNA demonstrated a 95% efficacy against SARS-CoV-2 one week after administering both the doses.

4. BNT162b2 phase-3 clinical trials were published in the New England Journal of Medicine (NEJM),suggesting that it protects from severe COVID-19.

B. Replication-defective viral-vector vaccines: Ad5-nCoV (CanSino Biological/Beijing Institute of Biotechnology).

1. They used human adenovirus serotype 5 vector (Ad5) to deliver the information that codes for SARS-CoV-2 full-length spike protein into host cells.

2. Ad5 is the main adenoviral serotype in humans, meaning that a significant percentage of individuals may have recent contact, and thus, pre-existing immunity against the viral vector could hamper robust immune responses against the CoV-2 full-length spike protein.

3. Intranasal administration of Ad5-nCoV was shown to be more immunogenic and induce earlier peaking of neutralizing antibodies compared to intramuscular vaccination.

4. The two lower doses of 5 × 1010 and 1 × 1011 viral particles were found to have an acceptable safety and immunogenicity profile and have been selected for a Phase-2 trial by FDA.

C. AZD1222 (AstraZeneca/Oxford University).

1. The viral vectored vaccine of Oxford University and AstraZeneca represents another candidate vaccine.

2. It was one of the first to begin clinical trials and the only one using a debilitated chimpanzee adenovirus (ChAdOx1).

3. To circumvent the issue of pre-existing immunity against Ad5, since very few -if any- humans would have a previous contact with a simian virus. The ChAdOx1 was engineered to include the wild-type SARS-CoV-2 Spike protein.

4. BALB/c and CD1 mice models immunized with two-doses of intramuscular injection of AZD1222 mounted strong humoral and cellular antigen-specific responses.

5. Phase 3 efficacy and safety trials with the two-dose regimen (Clinical Trial Identifier: NCT04516746) is being carried out in more than 30,000 individuals in countries such as India (Clinical Trial Identifier: CTRI/2020/08/027170), U.S., Brazil (Clinical Trial Identifier: ISRCTN89951424), Russia (Clinical Trial Identifier: NCT04540393), and South Africa.

D. Covaxin/BBV152 (Bharat Biotech/ Indian Council of Medical Research (ICMR) /National Institute of Virology (NIV))

1. India-based Bharat Biotechand the Indian Council of Medical Research (ICMR) developed a purified inactivated whole-virion vaccine candidate namelyCOVAXIN.

2. This vaccine was developed by β-propiolactone inactivation of an Indian-strain of the novel coronavirus isolated by the National Institute of Virology, Indiaand propagated in Vero-CCL-81 cells.

3. Neutralizing sero-conversion rates were 93.4% and 86.4% in the 3μgand 6μgadjuvant with alum and imidazoquinoline groups, respectively versus 86.6% in the 6 μgalgel-only group.

4. The COVAXIN under Registration Number: CTRI/2020/11/028976 in India is under phase-3 clinical trial.

E. DNA vaccines: INO-4800 (Inovio/International Vaccine Institute)

1. Pennsylvania-based company Inoviohas not yet officially entered Phase 3 trials. This candidate vaccine is the most advanced SARS-CoV-2 DNA vaccine so far.

2. However, FDA had put the planned Phased 2/3 clinical trials of the vaccine candidate on a partial hold due to questions about the design and use of Cellectra 2000

3. They have developed several experimental DNA-based vaccines which are administered intradermally with the aid of a portable device called ‘Cellectra 2000’ that delivers a small electric pulse allowing for efficient cellular and nuclear uptake of the DNA molecules through an electroporation.

4. 1.0−2.0 mg of INO-4800 four-weeks apart mounts strong humoral responses in volunteer participants.

5. FDA has given them permission to move forward with their Phase 2/3 trial called INNOVATE65 (Clinical Trial Identifier: NCT04642638).

F. Gam-COVID-Vac/Sputnik V (Gamaleya Research Institute/Health Ministry of the Russian Federation/Acellena Contract Drug Research and Development).

1. Scientists of the Russian Research Institute Gamaleya developed the only heterologous prime-boost SARSCoV-2 vaccine candidate thus far in order to circumvent the challenge of reduced immunogenicity due to antibodies raised against the viral vector after the first immunization.

2. The adenoviral vector serotype used for the prime vaccination is different from the adenoviral serotype used as a booster. Hence, replication-defective Ad26 was selected to deliver the genetic information for SARSCoV-2 Spike protein during the first vaccination and recombinant replication-defective Ad5 for the second.

3. On November 24th, the developers of Sputnik V announced the results from their second Phase 3 interim report, revealing a 91.4% efficacy of this vaccine candidate after analysing the data.

Note: This vaccine is much better than the previously generated vaccines.

Take home message

1. There are currently more than 230 vaccine candidates under development, with a number of these already receiving EUAs within less than a year since the first report of a SARS-CoV-2 infection.

2. All the leading vaccine candidates are administered via intramuscular injection. However, results emerged from several recent studies highlighting the importance of mucosal immune responses against SARS-CoV-2 infection (Hassan, A. O. et al., CELL, 2020).

3. The vast majority of SARS-CoV-2 vaccines under development require a prime-boost regimen.

4. Massive vaccination campaigns would therefore require billions of doses to satisfy global demand.

5. High vulnerability groups such as health workers and indispensable professionals are the first to receive a vaccine, followed by age groups older than 65 years.

6. Nucleic acid and -sometimes- viral vector platforms that require long-term storage at −70 °C from fabrication to administration can raise severe problems for the distribution of the respective vaccines and limit their use in rural areas (Nikolaos C. Kyriakidis et al., 2021. Nature Vaccines).

7. Children and pregnant women and other vulnerable groups, who are at bay from clinical trials conducted so far. It is quite probable that these groups will have to wait for additional small-scale clinical trials after the first generation of vaccines will be approved (Nikolaos C. Kyriakidis et al., 2021. Nature Vaccines).

8. To my personal observation, SARS-CoV2 persistent infected person, SARS-CoV2 infected immuno-compromised persons like cancer patients, AML, CML, congenital immune-deficient person, those who were given antiviral SARS-CoV2 drugs, continuous antibiotics, pregnant women-folk, and paediatric group children should be kept under strict surveillance so as to dampen the anticipated SARS-CoV2 3rd spike.

9. Above all, we need to change our behaviour in order to keep the SARS-CoV2 and its variants at bay.

Dr Arif Bashir is a PhD in Clinical Biochemistry, Post-Doctorate in Cancer-Stem Cell Biology, and invited referee of Springer’s Tumor Biology, The Netherland. Email: bashir.aarif@gmail.com

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