Vaccination is the process of administering a vaccine, i.e., a biological substance intended to stimulate a recipient’s immune system to produce antibodies or to undergo other changes that provide future protection against specific infectious diseases. Immunization is the stimulation of changes in the immune system through which that protection occurs. These two concepts differ slightly in that administration of a vaccine may not always result in satisfactory immunization (protection) and that immunization may sometimes occur as a result of processes other than administration of a vaccine, e.g., through the body’s immunologic response to natural illness or through injection of preformed antibodies from an external source.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)/COVID-19  outbreak that started in Wuhan, China, in 2019 resulted in a pandemic not seen for a century and there is an urgent need to develop safe and efficacious vaccines. The scientific community has made tremendous efforts to understand the disease and unparalleled efforts are ongoing to develop vaccines and treatments. Toxicologists and pathologists are involved in these efforts to test the efficacy and safety of vaccine candidates. Presently, there are several SARSCoV-2/COVID-19 vaccines granted for emergency use and several other vaccines are in clinical trials. The pace of vaccine development has been highly accelerated to meet the urgent need.

To date, enhanced disease has not been observed with SARSCoV-2/COVID-19 vaccines in preclinical models or humans. However, vaccine-related enhanced disease was reported after some viral infections and following vaccination against some viruses, including in animal models administered SARS-CoV-1 and MERS vaccine candidates which appear to be due to Th2-type responses. This has raised concerns of a potential theoretical risk with SARS-CoV-2/COVID-19 vaccines. Enhanced disease can be associated with antibody dependent enhancement (ADE), which involves the binding of antibodies to the virus to form an antibody/virus complex which enhances viral entry into macrophages and other immune cells. As reviewed by Smatti and colleagues in 2018, this was originally reported in 1964 with a flavivirus although it has been shown to occur with a wide variety of viruses since then. Viral pathogenesis is closely interlinked with host’s immune response and a better understanding of the virus–host dynamic is important in the development of safe and efficacious vaccines. Viral infections are associated with different types of antibodies including neutralizing, enhancing, non-neutralizing, and non-enhancing antibodies. There are several viral factors that are important in enhanced disease such as viral type, strain and surface proteins which are the predominant contributors to antibody development. There are also host factors of relevance such as T and B cell responses and specifically the antibody titre, type and class and the presence of complement. The host’s genetics may also be relevant, including polymorphism in genes associated with innate and adaptive immune responses to viruses such as cellular receptor genes including Fc gamma receptor (FcgR) and major histocompatibility complex (MHC), as well as genes related to cytokine and complement pathways. Another mechanism by which enhanced disease may occur after viral infection is associated with the development of a Th2-type immune response, rather than the protective Th1 response needed to effectively eliminate the pathogen. Previous vaccine development efforts (in the 1960s) with a formalin-inactivated vaccine for respiratory syncytial virus (RSV) demonstrated the potential for vaccine-associated enhancement of disease. RSVs–naive children were administered the formalin-inactivated whole virus vaccine candidate (FI-RSV) and experienced vaccine-enhanced disease (characterized by an increased frequency of infection and/or increased severity of respiratory disease) upon subsequent natural exposure to RSV, with the death of 2 FI-RSV-vaccinated infants (following a natural infection at 16-18 months of age). RSV mediated disease enhancement was not observed in individuals previously infected with RSV, regardless of subsequent immunization. His to morphologic features in the lungs of humans included inflammatory response (predominantly neutrophils and eosinophils) with evidence of immune complex formation and complement activation. Subsequent research in animal models showed similar features in mice, and the immune response was characterized as Th2 dominant, with a poorly neutralizing antibody response. This was different from the ADE described for viruses with tropism for macrophages, such as the human dengue virus (a flavivirus) and feline infectious peritonitis (FIP) virus in cats (a coronavirus).

Recently, a group of vaccine immunologists and coronavirus experts (convened by the Coalition for Epidemic Preparedness Innovations and the Brighton Collaboration Safety Platform for Emergency Vaccines) made recommendations regarding vaccine design considerations for efficacy and safety, assessment of the immune profile of SARS-CoV-2/COVID-19 vaccines and how to assess safety risks such as enhanced disease using animal models and immunological assessments in early clinical trials. Unfortunately, in vitro assessment for ADE is not a reliable predictor of enhanced disease in humans. The experts believe the mechanism of disease enhancement involves non-neutralizing or incompletely neutralizing antibodies (based on the role in developing immune complexes and Fc-mediated viral capture by monocytes/macrophages) and recommended selecting vaccine candidates that elicit strong neutralizing antibodies, together with a Th1 dominant responses and balanced CD4/ CD8 and poly functional T-cell responses (avoiding those with Th2 dominant response and non-neutralizing antibodies). 

In National Health Plan(NHP) studies with various vaccine candidates such as AstraZeneca PLC/University of Oxford, adenoviral vector vaccine candidate and Moderna Inc’s messenger RNA [mRNA]-1273 vaccine candidate, vaccination followed by viral challenge resulted in robust SARS-CoV-2 neutralizing activity, Th1-biased CD-4 T-cell responses, and protection against viral replication in the upper and lower airways, without any evidence of enhanced disease. Emerging clinical trial data with SARS-COV-2/COVID-19 mRNA vaccines formulated in lipid nanoparticle (Moderna Inc and Pfizer Inc/BioNTech) demonstrate viral neutralization responses and Th1-skewed T-cell responses in humans. In an National Health Plan(NHP) study with an adenoviral vector–based vaccine candidate (Johnson & Johnson/Harvard Medical School) expressing the spike protein, a strong neutralizing antibody response and Th1-biased T-cell responses occurred after a single immunization. Although enhanced disease has not been reported in any animal models or clinical trials with SARS-CoV-2/COVID-19 vaccine to date and is considered low risk for SARS-COV-2/COVID-19 vaccines, regulatory agencies expect sponsors to carefully evaluate the potential/ theoretical risk for enhanced disease in preclinical and clinical studies for vaccine candidates.

There are some practical challenges in the assessment of efficacy and enhanced disease in animal studies, such as the need for a BSL-3 facility to conduct animal efficacy studies and the lack of ideal animal models that fully recapitulates severe COVID-19 disease in humans or model enhanced disease.  Most animal models do not develop notable lung disease, and viral infection is typically monitored by molecular methods (such as reverse transcription–polymerase chain reaction – RTPCR) to detect virus levels in nasal swabs, bronchoalveolar lavage, feces, or tissues. It is important to use sufficient group size and appropriate positive and negative controls. Developing a standardized study design with consistent study end points would significantly improve data comparisons between studies across the industry and academia.  

Albeit, COVID-19 disease vaccine candidate vaccination followed by viral challenge resulted in robust SARS-CoV-2 neutralizing activity, an ideal vaccine characteristics not elicited from currently  available emergency sanctioned vaccines which are developed by scientists and researchers around the globe. The consideration of an “ideal” vaccine’s characteristics can help provide some perspective on the shortcomings and challenges of current vaccines For example, many-most-current vaccines require more than a single dose for a complete regimen and then require booster doses at various intervals. Vaccines that are freeze dried or that otherwise do not require strict refrigeration greatly simplify the design and requirements of national immunization programs. Similarly, vaccines (such as oral polio vaccine or oral typhoid vaccine) that do not require injections have a great theoretical advantage over vaccines requiring needles and syringes for administration.

As we are seeing devastation stages in human lives due to COVID-19 pandemic, the scientists/researchers must recommend vaccine which have “Ideal” vaccine characteristics such as • Vaccine is highly immunogenic, so that a single vaccine dose provides a complete immunization regimen. • The recommended vaccine regimen is highly efficacious in preventing disease in individual vaccine recipients, including recipients with weakened immune systems from HIV infection, severe malnutrition, malignancies, or congenital immunodeficiency. • It has a long duration of immunity, so that frequent booster doses are not needed. • It limits spread of infection, because it prevents vaccine recipients from spreading infection to other people. • It is heat stable, so that refrigeration (“cold chain”) is not required during shipping and storage. • Injection is not required for administration, e.g., a nasal spray of vaccine can be used. • It can safely be administered simultaneously with other vaccines, either as a part of a specific combination vaccine (e.g., measles-mumps-rubella) or as separate individual vaccines. • Adverse effects in vaccine recipients are few, non severe, and temporary; in particular, the microbe used to prepare the vaccine does not cause disease in recipients who have immune systems weakened by HIV infection, severe malnutrition, malignancies, or con-genital immunodeficiency. • The microbe used to prepare the vaccine never reverts to “wild type” or otherwise mutates to cause disease in vaccinated people or in their close contacts. • It is technically simple to manufacture, so that it can be produced in less sophisticated settings. • It is inexpensive to manufacture, distribute, and administer, so that it is affordable by the maximum number of people.

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