# Vaccine Advice
So it seems there has been a fairly consistent precedent concerning coronavirus vaccine development, involving the spike protein in particular, wherein the technology tested was both eliciting an antibody response while also demonstrating a greater chance of fatal disease in the case that the organism later contracts SARS Cov and its analogues.

Excerpts include:
1. https://www.sciencedirect.com/science/article/pii/S0264410X08015053?via%3Dihub:
- Examples of vaccine-induced enhancement of susceptibility to virus infection or of aberrant viral pathogenesis have been documented for infections by members of different virus families. Several mechanisms, many of which are still poorly understood, are at the basis of this phenomenon. Vaccine development for lentivirus infections in gelera, and for HIV/AIDS in particular, has been little successsful. Certain experimental lentiviral vaccines even proved to be counterproductive: they rendered vaccinated subjects more susceptible to infection rather than protecting them. For vaccine-induced enhancement susceptibility to infection with certain viruses like feline coronavirus, Dengue virus, and feline immunodeficiency virus, and it has been shown that antibody-dependent enahcement (ADE) plays an important role. Other mechanisms may, either in the absence of or in combination with ADE, be involved. Consequently, vaccine-induced enhancement has been a major stumble block in the development of certain flavi-, corona-, paramyxo-, and lentivirus vaccines. Also recent failurs in the development of a vaccine against HIV may at least in part be attributed to indection of enhanced susceptibility to infection. THere may well be a delicate balance between the induction of protective immunity on the one hand, and the induction of enhanced susceptibility on the other. The present paper reviews the currently known mechanisms of vaccine-induced enhancement of susceptibility to virus infection or of aberrant viral pathogenesis.

2. https://www.sciencedirect.com/science/article/pii/S2214750020304248

Calina et al. evaluated the ongoing approaches to COVID-19 vaccine development, and stated: "Normall, the period of development of a vaccine is 12-15 years". Against this backdrop, SARS-CoV2 vaccines are targeted for accelerated development, safety testing, manufacturing, and distribution by an order of magnitude. Each of the accelerated steps has drastically reduced the tim required for normal development. Some of the potential adverse vaccine effects shown on the right of Fig1 may take years to emerge, well after the initial abbreviated vaccine safety testing period.
(From fig1):
- Antibody-Dependent Enhancement
- Immune Enhancement
- Cross-reactivity
- Non-Specific Vaccine Effects on Immune System
- Antigenic Distant Hypothesis
- Bystander Activation
- Immune Evasion
- Immune Interference
- Chronic Immune Activation
- Impact of Combinations of Toxic Stimuli

3.2 Past coronavirus vaccine development history

There have been two prior coronavirus outbreaks in the 21st century: SARS in 2002-2003, and MERS starting in 2012. Vaccine development for each started/accelerated during the height of each outbreak. What have been the results of these prior coronavirus vaccine development efforts?

According to a comprehensive 2019 article on MRS vaccine development, "To date, there is no specific treatment proven effective against this viral disease. In addition, no vaccine has been licensed to prevent MERS-CoV infection thus far ... In general, the potential vaccine candidates can be classified into six types: viral vector-based vaccine, DNS vaccine, subunit vaccine, nanoparticle-based vaccine, inactivated-whole virus vaccine and live-attenuated vaccine"

Accoring to a comprehensive 2020 article on SARS and MERS vaccine development, "As of April 2020, no vaccine is commercially available for these coronavirus strains". The rationale for lack of a vaccine is given by the following: "Reasons for the lack of commercial and effective vaccines for SARS and MRS are varied. In the case of MERS, it is likely that the vaccine development was delayed because of the scarcity of suitable and cost-effective small animal models during pre-clinical experimentation. In addition, it is probable that a vaccine has not been delivered that has produced relatively low and geographically centralize cases (compared with other more global and persistent infectious diseases such as influenza, HIV and tuberculosis). This last factor might have also contributed to the lack of a vaccine for SARS, in the sense that it was considered pointless to continue investing in a vaccine for a disease whose cases ceased to be reported in 2004."

While interest in a vaccine may have waned after the SARS pandemic/outbreak seemed to have terminated, research on such a vaccine persisted. References in the above article showed SARS vaccine researched continued for a decade or more fater the pandemic had ended.

Based on experiences with SARS and MRS, successful vaccine development was not achieved after aout a decade of research, or even more. That does not bode well for COVID-19 coronavirus vaccine development/safety testing/distribution for hte one-year timescales being projected.

3.3 Challenges for successful vaccine development - overview

The main challenges facing successful coronavirus vaccine development can be summarized as time to development, efficacy of the vaccine and, most importantly, safety of the vaccine. A complementary perspective on some of the problems listed in [41] can be stated as follows:

First, although the virus' spike protein is a promising immunogen for protection, optimizing antigen design is critical to ensure optimal immune response. Debate continues over the best approach - for example, targeting the full-length protein or only the receptor-binding domain.

Second, preclinical experience with vaccine candidates for SARS and the Middle East respiratory syndrome (MERS) have raised concerns about exacerbating lung disease, either directly or as a result of antibody-dependent enhancement. Such an adverse effect may be associated with a type 2 helper T-cell (Th2) response. Hence, testing in a suitable animal model and rigorous safety monitoring in clinical trials will be clinical.

3.4 Vaccine mechanisms with uncertain consequences

Numerous mid- and longer-term potential issues concerning vaccines have been identified. Their themes rae summarized initially, followed by excerpts from specific cited references.
1. Antibody-Dependent Enhancement (where enhanced virus entry and replication in a number of cell types is enabled by antibodies)
  a) Intrinsic Antibody-Dependent Enhancement (where non-neutralizing antibodies raised by natural infection with one virus may enhance infection with a different virus)
  b) Immune Enhancement (enhancement of secondary infections via immune interactions)
  c) Cross-reactivity (an antibody raised against one specific antigen has a competing high affinity toward a different antigen.)
  d) Cross-Infection Enhancement (infection enhancement of one virus by antibodies from another virus)

2. Vaccine-associated Virus Interference (where vaccinated individuals may be at increased risk for other respiratory viruses because they do not receive the non-specific immunity associated with natural infection)

3. Vaccine-Associated Imprinting Reduction (where vaccinations could also reduce the benefits of 'imprinting', a protection conferred upon children who experienced infection at an early age)

4. Non-Specific Vaccine Effects on Immune System (where previous infections can alter an individual's susceptibility to unrelated diseases);

5. Impact of Infection Route on Immune System (where immune protection can be influenced by the route of exposure/delivery.)

6. Impact of Combinations of Toxic Stimuli (where people rae exposed over their lifetime to a myriad of toxic stimulii that may impact the influence of any vaccine);

7. Antigenic Distance Hypothesis (negative interference from prior season's influenza vaccine (v1) on the current season's vaccine (v2) protection may occur when the antigenic distance is small between v1 and v2 (v1 ~ v2) but large between v1 and the current epidemic strain (v1 != e);

8. Bystander Activation (activation of T cells specific for an antigen X during an immune respones against antigen Y)

9. Gut Microbiota (impact of gut microbial composition on
vaccine respones)

10. Homologous Challenge Infection Enhancement (the strain of challenge virus used in the testing assay is very closely related to the seed virus strain used to produce the vaccine that a subject received).

11. Immune Evasion (evasion of host respone to viral infection)

12. Immune Interference (interference from circulating antibody to the vaccine virus).
  a) Original antigenic sin (propensity of the body's immune system to preferentially utilize immunological memory based on a previous infection when a second slightly different version of the foreign entity (a virus or bacterium) is encountered.)

13. Prior Influenza Infection/Vaccination (effects of prior influenza infection/vaccination on severity of future disease symptoms).

14. Timing between Viral Exposures (elapsed time between viral exposures)

15. Vaccine-Associated Enhanced Respiratory Disease (where vaccination enhances respiratory disease)

16. Chronic Immune Activation (continuous innate immune responses)

# Summarized in short list:
- ADE
- Immune Enhancement
- CR (competing affinity for different antigen)
- CIE (enhancement of one virus by antibodies from other virus)
- Vaccine-associated Virus Interference (loss of non-specific immunity)
- Vaccine-Associated Imprinting Reduction