COVID-19 Vaccine Development and Delivery: The Nemesis, the Hubris, and the Elpis

The Nemesis – SARS-CoV-2 Pandemic: Leaving in its wake millions of infections, accompanied by an immense magnitude of morbidity and multitude of mortality, and an unfathomable economic toll, the COVID-19 pandemic has led to a global impact. A vaccine is urgently needed to prevent the disease, thwart the complications and avert deaths resulting from transmission of the infection. The Hubris – Vaccine Development: While most of the platforms of vaccine candidates have focused on the spike (S) protein and its variants as the primary antigen of COVID 19 infection, various techniques involved include nucleic acid technologies (RNA and DNA), non-replicating viral vectors, peptides, recombinant proteins, live attenuated viruses, and inactivated viruses. There are novel vaccine technologies being developed for COVID 19 using next-generation strategies for precision and flexibility for antigen manipulation on SARS-CoV-2 infection mechanisms. The Elpis - Updates and Prospects: There were nine different technology platforms under research and development to create an effective vaccine against COVID 19. Although there are no licensed vaccines against COVID-19 yet, there are various potential vaccine candidates under development and advanced clinical trials. Out of them, few having undergone phase III clinical trials, may soon be available for use among the high-risk groups following emergency use authorization. Conclusion – Hopes and Concerns: the the it the and the COVID-19 pandemic, is accompanied by the likely fear of adverse effects and opposition in public for COVID-19 vaccination, including the vaccine hesitancy. Further, there is concern among scientific circles that vaccine may have opposite of the desired effect by causing antibody-dependent disease enhancement.

of SARS-CoV-2 binding and neutralizing antibody titres and their ability to predict efficacy is needed to be evaluated and confirmed.
Though the immune correlates of protection against SARS-CoV-2 are yet to be determined, the neutralising antibodies are thought to be associated with protection based on results from studies in COVID-19 non-human primate challenge models inferring that neutralising antibody response is correlated with protection [4].
These findings have led to the use of neutralisation assays to assess immune responses in recent human COVID-19 vaccine trials [5].

The Nemesis: SARS-CoV-2 Virus Invasion and the Pandemic
The Virus and the Disease During December 2019, an outbreak of apparently viral pneumonia was reported in the city of Wuhan, in Hubei province in China. Soon the disease spread to other parts of China and several countries to become a pandemic. By 9 January 2020, it was established that the disease was caused by a novel coronavirus, 2019-nCoV or SARS-CoV-2 and was named COVID-19 [6]. Later, during the first half of January 2020, the Chinese researchers shared the genome sequence of the virus, followed by identification of the same by the Mutualized Platform for Microbiology (P2M), Pasteur Institute, Paris on 29 January 2020 from the samples taken from the initial suspected patients in France [7]. Following the sequencing of SARS-CoV-2 genome, an international response was triggered to develop a prophylactic vaccine to provide acquired immunity against COID-19. By April 2020, almost 80 companies and institutes in 19 countries were working on the vaccine for COVID-19. Initially it was said, including by WHO in February 2020, that it did not expect a vaccine for the disease to become available in less than 18 months. Later, it has been claimed by researchers that with the help of genetic Engineering, the COVID-19 Vaccine can possibly be made in months rather than years [8].
Various vaccines under development to combat the  have been modelled on the original strain, which was common among hCoV-19 genetic sequences published during the initial months of the course of the disease pandemic. Understanding the evolution and mutations of SARS-CoV-2 during the COVID-19 pandemic is imperative for disease control and prevention through the vaccine programme. A spike protein mutation D614G has emerged supplanting aspartic acid (D) in the 614th position of the amino acid with glycine (G), hence the change known as D614G.
The D614G mutation has supposedly enhanced viral replication in human airway tissues, enhanced viral survival in the upper airway of infected hamsters, and increased susceptibility to neutralization.
It appears that the mutation may have increased the infectivity of the virus [9]. The work by Plante et al underlines the importance of this mutation in viral spread, vaccine efficacy, and antibody therapy [10]. It has been pointed out, the vaccines against COVID-19 are hoped to work against new G-strain, as well [11]. Further, the study involving Hamsters concluded that the D614G mutation may not reduce the ability of vaccines in clinical settings to protect against COVID-19 and the neutralizing antibodies are to be assessed against the circulating variant of the virus before clinical development.

SARS-CoV-2 Genomic Sequencing
The genome of SARS-CoV-2 is comprised of a single-stranded positive-sense RNA. It is composed of 13-15 (12 functional) Open Reading Frames (ORFs) containing ~30,000 nucleotides and contains 38% of the guanine-cytosine (GC) content and 11 proteincoding genes, with 12 expressed proteins [12]. The ORFs are arranged as replicase and protease (1a-1b) and major S, E, M, and N proteins. These gene products play important roles in viral entry, fusion, and survival in host cells. Basically, the genomic sequencing is a technique to interpret genetic information found within the virus. So far, there are over 1,000 COVID-19 genomes published worldwide [13]. The genomic sequencing helps in understanding when and where the version of the virus originated and how the virus is evolving. Sequencing the genome of SARS-CoV-2 virus also helps in understanding the disease transmission kinetics, its spread in population groups and planning and evaluating the containment efforts. In addition, it helps to track the viral mutations as the disease spreads. In general, the viruses circulating locally have small genetic changes compared to the ones that are circulating elsewhere. Thus, the genomic sequence can be used to estimate the infected population size and how the virus is spreading. Further, understanding of the genomic structure of the virus helps in developing drugs and vaccines for therapy as well as prophylaxis of COVID-19.

COVID-19 Vaccine Platforms
While most of the platforms of vaccine candidates have focused on the spike (S) protein and its variants as the primary antigen of COVID 19 infection, various techniques involved include nucleic acid technologies (RNA and DNA), non-replicating viral vectors, peptides, recombinant proteins, live attenuated viruses, and inactivated viruses [14]. The main protein, S protein to boost the immune system can be given as a vaccine in many different forms such as inactivated (dead) virus, as expressed protein, in a DNA or RNA vector that will lead the cells to make this protein and stimulate to make antibodies and activate T cells to control the viral infection or eliminate the infected cells to reduce disease severity and complications ( Figure 1). As reported during September 2020, there were nine different technology platforms (Table 1) under research and development to create an effective vaccine against COVID 19 [15]. There are novel vaccine technologies being developed for COVID 19 using next-generation strategies for precision and flexibility for antigen manipulation on COVID 19 infection mechanisms [16].

The Efficacy of the COVID-19 Vaccines
The effectiveness of a new vaccine is defined by its efficacy [20].
The minimal efficacy limit set by WHO is 50 percent. Whereas an efficacy of less than 60 percent may fail to achieve herd immunity.

The Elpis: Vaccine Updates and Future Scenario for COVID-19
The

Vaccines in Advanced Stages of Clinical trials
Out of various COVID-19 vaccine candidates in preclinical and clinical trials, only some are in advanced stages of clinical trials including 11 in phase 3 trials and few vaccine candidates are due for emergency use authorization (Table 2). to the data from the preclinical stage, the vaccine was found to be immunogenic in multiple animal species and the antibodies produced were able to completely neutralize the wild type virus.
In the Phase I clinical trials, the vaccine candidate was found to be safe and well tolerated. The vaccine is expected to be available

COVID-19 Vaccination -Other Issues
The Fast Tracks for COVID-19 Vaccines: Because of the urgency created by the COVID-19 pandemic, the development of various vaccines is on a fast track. Classically, for a vaccine the preclinical stage is about 18 to 30 months, followed by the phase I, II and III, each of them lasting for about two and half years, and the approval followed by production of the vaccine taking a period of another one to two years. For the COVID-19 vaccines being developed urgently, the preclinical stage is short one, followed by phase I and II each compressed to duration as short as 6 months and the phase III shortened to zero month, and the COVID-19 vaccine is foreseen to get an approval for emergency use and start its production simultaneously. The urgency and the haste are likely to involve errors at multiple stages and carry a potential scope for disaster.

Timeline for the COVID-19 Vaccination:
It is being envisaged challenge. It is also accompanied by issues such as its cost and who will be paying for it. In a Medscape reader poll involving 308 UK physicians, it was found that 4 in 10 doctors would not have a COVID-19 vaccine as soon as one is approved by the Medicines and Healthcare products Regulatory Agency in the country. About 56% cited safety concerns, 27% would rather wait, 7% mentioned personal health reasons, and 14% had other reasons. Overall, 59% said vaccination for healthcare staff should not be compulsory [24].
With the growing number of people who oppose the vaccination, their attitudes have also changed over last few months. The polling by Kantar of 1000 people carried out recently on 10-11 November, found that 76% of people in Britain would like to take a vaccine for COVID-19, but the score has fallen since June 2020.
In another European survey, 73.9% participants were willing to get vaccinated against COVID-19 if a vaccine would be available; 18.9% of respondents stated that they were not sure, and 7.2% stated that they do not want to get vaccinated [25]. The common reasons for opposing COVID-19 vaccination, are based on the belief that the vaccine may not be safe (24%), the concern about the side effects (21%), considering the COVID-19 infection not dangerous (14%), rejecting vaccinations as a general principle (11%), and some (8%) not willing to meddle with the course of the Nature [26].

The COVID-19 Vaccine Nationalism
The

Efficacy Vs Exaggerated Immune Reactions
The confirmation of the correlation between antibody titres and protection against Covid-19 can only be possible through a large clinical efficacy study. In the meantime, the assays for measuring antibody may fill the gap but their validity needs to be ascertained.
There is an uncertainty relating to the expected efficacy. It is being projected, depending on the profiles observed for other viral vaccines, that the vaccine's efficacy against severe COVID-19 may be higher than efficacy against mild disease. But there is another aspect of the immunological response to the vaccine. Although the antibody production by a potential vaccine is intended to neutralize the COVID 19 infection, it is feared that the vaccine may have an opposite effect by causing Antibody-Dependent Disease Enhancement (ADE), which might trigger the cytokine storm in case the person is infected by the virus in future, after the vaccination [30]. The technology used for vaccine, its dose, timing of repeat vaccinations for the possible recurrence of COVID 19 infection, and elderly age are factors related to the risk and extent of ADE.

The Vaccine Hesitancy and Concerns
The rapid development and urgency of producing a vaccine for the COVID 19 in view of the raging pandemic may increase the risks and failure rate of delivering a safe and effective vaccine. There are indications that the potential success rate may be only 10% for various COVID-19 vaccine candidates under development [31].
On the other hand, at least 10 per cent of the people in different surveys perceive the COVID-19 vaccines as unsafe or unnecessary and consider refusing the vaccination. This public perception has been called vaccine hesitancy [32]. Such behaviour can increase the risk of further viral spread that could lead to future COVID 19 outbreaks. As per a survey in the United States about 67% or 80% of people would accept a new vaccination against COVID 19, with wide disparity relating to education level, employment status, and racial and geographical background [33]. Similar and comparable findings have been documented in a study from the United Kingdom [34].