Brief Overview of Novel Human Coronaviruses

Coronaviruses are a large family of viruses. There are hundreds of coronaviruses, most of which infect only animals (commonly pigs, camels, bats and cats); but there are only seven coronaviruses that infect people: four usually cause only mild to moderate upper-respiratory tract illnesses, like the common cold, and three can cause more serious, even fatal disease. 

 

The three coronaviruses which can cause serious or fatal disease are all novel, or new, and are zoonotic viruses transmitted from animals to humans by virus spillover. The first novel coronavirus initially presented in southern China in November 2002 as a case of atypical pneumonia termed severe acute respiratory syndrome (SARS). In February 2003, it was discovered that the virus causing SARS was a novel coronavirus (SARS-CoV). With the mortality rates of SARS as high as 15% in some age groups, SARS caused panic in countries of East and Southeast Asia. Late November 2003, SARS-CoV was detected in masked palm civets from animal markets in Shenzen, China, so on January 13, 2004, the United States Center for Disease Control (CDC) issued "Notice of Embargo of Civets" which banned the importation of civets.  By May 2004, SARS-CoV was considered eradicated. Several years later, studies revealed large numbers of SARS-related coronaviruses among China’s horseshoe bats, suggesting that SARS-CoV originated in bats, then passed to civets. Years later, post-pandemic analysis of the 2003 global SARS outbreak revealed two notable observations:  very few cases of SARS were reported among children and children younger than 12 years seemed resistant to SARS-CoV.

 

The second novel coronavirus, MERS-CoV, was first identified in June 2012. Middle East respiratory syndrome (MERS), is an acute respiratory disease like SARS, and presents with a wide range of clinical manifestations, often leading to pneumonia and renal failure. MERS-CoV is a spillover virus transmitted from bats and dromedary camels to humans. Due to regional people’s close contact with their camels, MERS-CoV is still infecting humans. As of December 2019, MERS-CoV has a case mortality rate 34.3%, with the mortality rate in children being significantly lower than in adults. With only a 2% pediatric infection rate, MERS is mainly a disease of adults.

 

The present outbreak of CoV infection was reported from Wuhan, China in late December 2019 as an atypical pneumonia of unknown case. An announcement from Chinese authorities on January 07, 2020, identified the causative pathogen as a novel coronavirus (CoV); soon thereafter, the new infection was referred to as COVID-19. On February 11, 2020 the World Health Organization (WHO) announced the new type of coronavirus as SARS-CoV-2 and soon after declared COVID-19 a global pandemic. Like SARS-CoV and MERS-CoV, SARS-CoV-2 is an acute respiratory disease which can be serious or fatal. Early analysis of SARS-CoV-2 pandemic demographic data revealed a feature similar to SARS and MERS: compared to adults, children had significantly lower rates of COVID-19 infection and their symptoms were fewer and milder.

General Concepts of Immunity

The body has network of defenses in place to avoid infection. These defenses, comprised of specialized proteins, cells, tissues, and organs, are collectively referred to as the immune system.  Immunity is the body's ability to recognize and destroy substances which it interprets as foreign and harmful (antigens); simply put, immunity is protection against disease. The most common immune response is the production of antibody. 

 

There are two main categories of immunity:  natural, or innate; and acquired, or adaptive. Natural/innate immunity can be further categorized as active or passive. Active immunity, whether natural or acquired, can have specific or broad action. 

Natural active  immunity refers to neutralizing antibodies (NAbs), broadly neutralizing antibodies (bNAbs) and antibodies acquired by previous infection. Having monovalent affinity, NAbs can be specific towards a viral species or specific antigen, whereas, bNAbs have the special ability to bind and neutralize different antigens or multiple strains of a virus species, which is an example of cross-reactive immunity.  

Cross reactive immunity, sometimes referred to as cross-immunity or cross-protective immunity, is a phenomenon of immunity: different antigens appear similar to the immune system, which causes an immune response – the result is either a complete response and no infection/disease, or a milder course of illness. 

Antibody is a specialized immune protein produced by the immune system in response to encountering an antigen.

Antigen is a substance (toxins, chemicals, bacterial, viruses, etc.) that cause an immune response, especially antibody generation.

Natural Active Immunity involves neutralizing antibodies (Nabs), broadly neutralizing antibodies (blabs) or antibodies acquired by previous infection.

Acquired Active Immunity is achieved by vaccination.

Natural Passive Immunity occurs by receiving antibodies from another natural source (e.g. mother to fetus via placenta or to newborn via breast milk).

Acquired Passive Immunity is a temporary immunity gained by receiving manufactured antibodies, such as immune globulin.

It appears that cross-immunity, specifically a cross-reactive active immunity acquired by vaccination, may be the key to the apparent resistance to COVID-19 seen in children and some adults. 

Brief History of Vaccines

Western history credits Dr. Edward Jenner for the first vaccine. However, the story of immunization begins with the long history of human infectious disease; in particular, with smallpox. Smallpox is the first disease for which a vaccine was produced. With a death rate of 30%, smallpox is one of history's most feared illnesses.

Awareness of acquired disease immunity dates back more than 2400 years. As early as 430 BC, it was known that survivors of smallpox became immune to the disease, so those who survived smallpox illness were called upon to tend to those who became newly afflicted.

From the mid-16th century, there are two accounts of inoculation, or variolation,  one Chinese and one Indian:

  • Documented in a book first published in 1549, the Chinese technique was to harvest smallpox scabs from a living infected person, then blow ground-up dried smallpox scabs up the nose of the healthy recipient.

  • The Indian technique was to infect the healthy recipient's skin with smallpox pus, either by dipping a needle into a smallpox pustule, then repeatedly puncturing the recipient's  skin; or by smearing smallpox pus or ground-up smallpox scabs into scratches made on the skin.

Variolation was also also practiced in Africa and Turkey, before it spread to Europe and the Americas in the 18th century. 

During the late 18th century (1796 - 1798), the first vaccine was developed by English physician Edward Jenner. For many years, he noticed that dairymaids and dairy farmers who had suffered from cowpox did not get smallpox. Jenner realized that cowpox could be used to deliberately protect people from smallpox - he could use a mild illness from cattle to protect humans from a deadly disease. Since his method of immunization was different than variolation, Jenner decided to term his new method 'vaccination.' Over the next 200 years, Jenner's method underwent medical and technological changes, and eventually led to the eradication of smallpox.

In the era of COVID-19 pandemic, there is value in revisiting Edward Jenner's discovery of cross-reactive immunity. 

Immunization: is the process or action of making a person or animal immune against disease, usually by inoculation. Often the terms immunization and inoculation are used interchangeably. 

Inoculation is to introduce immunologically active material (antibody or antigen), in order to treat or prevent a disease.

Variolation  is using the smallpox virus to inoculate an uninfected person (Latin: vari for 'pimples' and variola for 'smallpox').  

Vaccination: iDr. Edward Jenner was the first to use the term 'vaccination.' He decided to call his method 'vaccination' because it was derived from a virus affecting cows. (Latin:vacca for 'cow' and vaccinus for 'of or derived from a cow')

Cross-Reactive Immunity: different antigens appear similar to the immune system, which stimulates an immune response. The term is often used interchangeably  with cross-protective immunity.

Immunization and Vaccines

Immunization makes a person or animal immune to infection by copying the body’s natural immune response. Vaccines “teach” your body how to defend itself when a pathogen, an infectious agent such as a virus or bacteria, invades. By using a vaccine to expose you to a small, safe amount of a strategic subunit or weakened/killed pathogen, your immune system learns to make antibodies that will prevent illness, by recognizing, attacking and killing that pathogen if you are re-exposed to it: immunization helps keep the individual healthy and helps prevent the spread of disease.

 

Vaccination programs can be very successful: Global vaccination efforts have successfully eradicated smallpox in the western hemisphere. Yet, despite the proven success of concerted world-wide immunization, vaccination requirements vary between countries and within the United States.

 

Some vaccines are recommended while others are mandatory. Mandatory childhood vaccinations are required in order for children to attend school or daycare. Each state sets its own requirements, so there is some state-to-state variability among mandatory immunization schedules; however, six common childhood vaccinations required in all states. As a result of this commonality among the states, before starting school, 97-98% of US children are fully vaccinated against 6 diseases.

Vaccines Required by Law*

* The vaccines listed are those which are commonly required throughout the United States; some states require additional vaccinations for school.

Hepatitis B: In 1995, Advisory Committee on Immunization Practices (ACIP) recommended vaccinating children age  11–12 years. Then in 1999, ACIP recommended all children    < 19 years be vaccinated against HBV.

Varicella: In 1999, ACIP recommended establishing childcare and school entry requirements; then in June 2006 and June 2007, the ACIP recommended a 2-dose vaccination for  children, with the first dose given at age 12 - 15 months and a second dose at age 4 - 6 years.

Vaccines Recommended by CDC

 In the United States, apart from requirement under the Immigration and Nationality Act*, there are no mandatory  vaccines for adults, but some vaccines are recommended for adults depending upon age, specific health status, lifestyle and occupation. Vaccinations for hepatitis B and varicella are two good examples.

Hepatitis B Virus

Hepatitis B virus (HBV) attacks the liver and can cause both acute (hepatitis) and chronic disease (cirrhosis and hepatocellular carcinoma).  In July 1986, the first recombinant HBV vaccine was approved in the United States. Initially, the vaccine was recommended only high-risk populations such as healthcare workers. Then on November 15, 1991 the CDC expanded its recommendations to include immunizing infants. The following week, the Advisory Committee on Immunization Practices (ACIP) issued similar recommendations. Three months later, the American Academy of Pediatrics (AAP) published similar recommendations for universal hepatitis B immunization of infants. For both adults and infants, the vaccination schedule is a series of 3 shots given over 4 to 6 months.

* Since 1996, under Immigration and Nationality Act (INA), section 212(a)(1)(A)(ii), every immigrant entering the United States, or every individual seeking legal permanent resident status, is required to show proof of vaccination for the following diseases: measles, mumps, rubella, polio, pertussis, diphtheria, tetanus, haemophilus influenza type B, and Hepatitis B.

Varicella Zoster Virus

Varicella Zoster Virus (VZV) cause chicken pox and shingles. Two diseases arise from the same virus, but they afflict different populations: children are susceptible to chicken pox and immunocompromised or aging adults are vulnerable for shingles. 

  • In 1995, the chickenpox vaccine was added to the childhood immunization schedule as a single dose vaccine but, over time, it was found to provide only short term protection (90% effective the first year but only 70% effective after the third year); so, in 2006, a second dose was added to the childhood immunization schedule. The addition of a second dose, given around ages 4-6 years, has proven to 97% effective and provides longer lasting immunity, which has resulted in a drastic reduction in incidence of chickenpox.

  • For adults, there are two different types of vaccinations for varicella (VZV):  the one-dose vaccine uses live attenuated virus (alive but weakened virus), however it is only 50-63% effective. The newer vaccine, which is a two-dose subunit vaccine containing the VZV glycoprotein E subunit, is 97% effective at preventing herpes zoster (shingles) in people over 50. Correspondingly, the two-dose subunit shingles vaccine stays effective for longer than the single dose VZV vaccine

Virus Structure and Vaccine Design

Virus Structure and Vaccine Design

The body has a system of defenses to prevent infection and viruses have ways of avoiding detection. One way a virus can escape immune detection is to be enveloped. 

Viruses can be envelope or non-envelope. Envelope viruses hijack the host cells molecular machinery for reproduction. The viral envelope plays a critical role in the process of viral attachment and reproduction in the infected cells. Specific viral proteins, termed glycans, play important roles in virus infectivity (attachment and cell invasion) and virus protection from immune recognition or destruction.

All coronaviruses are enveloped, as are hepatitis B and varicella viruses.

As the principal determinant of viral infectivity, the viral envelope has been studied to a considerable extent. Glycans are an important feature of the virus envelope structure; especially N-linked glycans, O-linked glycans and mucin-like domains (MLD), which are known to shield the virus from immune recognition and affect infectivity.  

 

For the expressed purpose of this investigation, attention will be focused on SARS-CoV-2, hepatitis B virus (HBV) and varicella zoster virus (VZV).

SARS Coronavirus-2 (SARS-CoV-2)

 

Coronaviruses, including SARS-CoV-2, are enveloped viruses. Projecting from the surface envelop of the coronavirus are spike (S) glycoproteins which mediate viral attachment, binding and entry into host cells. The spike is also the main target of neutralizing antibodies.

The spike, or S protein, is common to the coronavirus family and responsible for virus attachment and entry into host cells. The spikes of SARS-CoV-2 are composed of two glycoproteins, termed S1 and S2: the S1 subunit is involved with binding the virus to the target cell and the S1 subunit is responsible for membrane fusion. The junction area between S1/S2 subunits, the cleavage site, seems to promote virus entry into host cells. 

 

Both SARS-CoV (SARS 2003 epidemic) and SARS-CoV-2 (COVID-19 pandemic) have envelope spikes which are heavily glycosylated with N-Linked glycans. However, there is a significant difference between the two SARS viruses:  the spikes of SARS-CoV contains only N-linked glycans whereas, the spikes of SARS-CoV-2 are heavily glycosylated with N-Linked glycans, except at the S1/S1 junction, or cleavage site, where there are three O-linked glycoproteins with a mucin-like domain (MLD) - this is thought to help shield the virus and avoid antibody recognition.

 

The spike is the main target of neutralizing antibodies, so it is important for vaccine design and therapeutic development.  Based upon the unparalleled success of the subunit vaccines for hepatitis B and shingles, the S1/S2 cleavage site ought to be the immune target area of interest for vaccine makers. At the present time, there are no FDA-approved vaccines for SARS-CoV-2.

Adapted from figure by Markus Hoffman

Hepatitis B Virus

Hepatitis is inflammation of the liver, which can be caused by viral infection, alcohol, toxins or autoimmunity. Hepatitis viruses are the most common cause of hepatitis in the world. There are five main hepatitis viruses (A, B, C, D and E) and there are important structural differences among these strains which impacts viral infectivity, pathogenicity and virulence:  hepatitis virus A, D and E are non-enveloped and have an ssRNA genome; hepatitis virus C in enveloped and has an ssRNA genome; hepatitis B is enveloped and has a ssDNA. Hepatitis B (HBV) is capable of causing both acute and chronic infection. Acute hepatitis B is usually self-limiting, but it can progress to chronic infection. Chronic HBV infection is a major cause of liver cirrhosis and hepatocarcinoma (HCC); both are associated with significant mortality. According to the World Health Organization, HBV is the most common-blood born infection globally and the second leading cause of cancer deaths in the world. In the United States, rates of new HBV infections are highest among adults aged 40-49 years.

 

HBV is highly contagious and virulent - as little as a single virion can lead to chronic HBV infection. The virulence of HBV is attributed to the HBV envelope gylcan structure. The infectious HBV virion (or Dane particle) is an enveloped virus. The HBV envelope consists of three similar proteins, small (S), medium (M), and large (L) proteins, which project from the surface like spikes. Collectively, the envelope proteins are known as hepatitis B surface antigen (HBsAg). HBsAg is heavily glycosylated wtih N-linked glycans except at the pre-S2 domain projecting from the M surface protein where it contains a section of O-linked glycans containing a mucin-like domain, which is thought to promote immune escape. The highly successful vaccine for HBV is a subunit vaccine that uses only HBsAg to confer immunity with a series of three injections given over 4-6 months. The development of the hepatitis vaccine marked two milestones for immunology: it is the first subunit vaccine and the first anti-cancer vaccine because it can help prevent liver cancer.

Adapted from Julithe R, Abou-Jaoudé G, Sureau C. Modification of the hepatitis B virus envelope protein glycosylation pattern interferes with secretion of viral particles, infectivity, and susceptibility to neutralizing antibodies. J Virol. 2014 Aug;88(16):9049-59. doi: 10.1128/JVI.01161-14. Epub 2014 Jun 4. PMID: 24899172; PMCID: PMC4136284.

Varicella Zoster Virus

Herpes is an infectious disease characterized by sores or clusters of small blisters on the skin, lips, or genitalia. There are more than 100 herpesviruses; nine of these are subcategorized as human herpesvirus because these exclusively infect humans. As members of the same virus species, human herpesvirus share a few key/significant features:  all are dsDNA viruses, enveloped with outward glycoprotein spikes or projections, and all cause latent infection. Varicella Zoster Virus (VZV), also known as HHV-3, is a member of the human herpesvirus (HHV) family. VZV infection causes varicella (acute infection) and shingles herpes zoster (reactivation of dormant virus). The initial infection with VZV results in chickenpox (varicella), which is typically seen in children younger than 10 years. During the initial infection phase, VZV quietly invades the cranial nerve and dorsal root ganglia sensory where it remains latent until it is reactivated. Years later, with age-related decline in immunity or when the individual is immunocompromised due to medical condition, VZV reactivates and causes neurologic disease such as herpes zoster (shingles). According to the most recent WHO position paper on varicella and herpes zoster vaccines, it is conservatively estimated that VZV-related disease causes 4.2 million severe complications requiring hospitalization.

 

VZV is highly contagious. As with other enveloped viruses, such as HBV, the virulence of VZV is attributed to its envelope gylcan structure. VZV is an enveloped virus with distinctive spikes composed of glycans, of which glycoprotein E is the most abundant. Glycoprotein E (gE) is crucial for VZV binding to host cell and essential for VZV replication. The structural organization of VZV gE is key to it’s infectivity and virulence:  VZV gE has two N-glycosylation sites joined by O-linked glycans with mucin-like domain (MLD), similar to SARS-CoV-2 spike S1/S2 junction site.

 

There are two types of varicella vaccines available: live attenuated virus vaccine and VZV gE subunit vaccine. Either vaccine is 97% effective in protecting against VZV infection, if given as a two-dose series. Despite global availability of VZV vaccine and WHO recommendations for universal routine vaccination programs to include varicella vaccine, most countries do not mandate the vaccine.In fact, childhood vaccination for varicella is mandatory only in the United States, Italy and Latvia.

Adapted from Nordén R, Nilsson J, Samuelsson E, Risinger C, Sihlbom C, Blixt O, Larson G, Olofsson S, Bergström T. Recombinant Glycoprotein E of Varicella Zoster Virus Contains Glycan-Peptide Motifs That Modulate B Cell Epitopes into Discrete Immunological Signatures. International Journal of Molecular Sciences. 2019; 20(4):954.

Virus Structure and Vaccine Design

infectious

viron

empty subviral

envelope particles

Hepatitis B

SARS CoV-2 (CoVid 19)

Varicella zoster

(chicken pox & shingles)

 

 

N/A

 

N/A

N/A

Credit: Published in Journal of investigative Medicine High Impact Case Reports 2018:  Varicella Pneumonia: Case Report and Review of a Potentially Lethal Complication of a Common Disease, John T Denny, Zoe M Rocke, et al.

Credit: CoVid 19 pneumonia by Dr Yair Glick

Credit: The Fellowship of Postgraduate Medicine: Self-assessment questions: Fever and dyspnoea in a young man with a rash. Varicella pneumonia.

Credit: Review of chest CT manifestations of COVID-19 infection: Maria El Homsia, Michael Chung, et al..

European Journal of Radiology Open Volume 7, 2020

Credit: Primary Varicella Pneumonia: Saul Krugman, M.D, Charles H. Goodrich, M.D,et al.  N Engl J Med 1957; 257:843-848 DOI: 10.1056/NEJM195710312571801

Credit: Getty Images

Credit: Robert Alain, SME, INRS-Institut Armand-Frappier

Credit:  Gerlich, Wolfram H. Medical Virology of Hepatitis B.  Virology journal 10. 239. 10.1186/1743-422X-10-239. 2013

electron

microscopy

photo

computer-

generated

illustration

Credit: The Lancet journals

Credit:  Jean-Yves Sgro/Visuals Unlimited, Inc

 entry into

 host cell​

entry into host cells is

mediated by the envelope

spike glycoprotein

envelope is studded with spikey glycoproteins which bind to specific host receptor and mediate virus entry

envelope glycoprotein spikes 

mediate the interaction of the virus

with cells and is essential for infectivity

vaccine

immunogen

vaccine pending

(not yet FDA approved)

glycoprotein gE

(the predominant glycoprotein of VZV  envelope and spikes​)

HBsAg

(the collective proteins of HBV envelope and spikes)

atypical

pneumonia

with 

 ground glass opacities 

seen on Xray

Credit: Cohen, J. P., Morrison, P. & Dao, L. Covid-19 Image Data Collection. arxiv 2003.11597 (2020)

Summary

Generally speaking, children seem resistant to SARS-CoV2

Children

 

Compared to adults, children seem relatively resistant to SARS-CoV-2 infection: regardless of comobidity, overall, children have less symptoms and a milder course of COVID-19.

Further analysis of the data revealed an overwhelming majority of pediatric COVID infection is seen in infants younger than 1 year.

Adults

For adults, generally, the risk of SARS-CoV-2 infection and the severity of COVID-19 disease correlates with comorbidities and advancing age. 

 

Incorporating parameters such as age and occupation, provides additional information:  

  • inconsistent infection rate and variable severity of COVID-19 symptoms among 19-25 year olds

  • some adults, especially those over 50 years old, also seem resistant to COVID-19

  • incidence of COVID-19 among healthcare workers is relatively low

Closer analysis reveals subcategories of resistant and at-risk populations:

Resistance to COVID-19 shows no geographical disparity. Despite state-to-state and county-to-county differences in pandemic-prevention practices, and variable onset of implementation of those practices, school attendance or home-schooling, etc., the COVID-19 age-related phenomenon is ubiquitous in the United States. Clearly, other factors besides age and exposure are affecting particular individuals’ immunity and resistance to SARS-CoV-2 infection. When these age and occupation related observations are superimposed on immunization policy or vaccination history of the last 30 years, an alternate theory for COVID-19 resistance becomes evident.  

Epidemics, Pandemics, Immunization Policy, and Vaccine History:  1986 - 2020 Timeline

 

In the years 1991-2017, the CDC made several adjustments to their immunization recommendation for HBV and VZV.

Some vaccines are recommended while others are mandatory. Each state sets its own requirements, consequently, mandated immunization schedules vary somewhat amongst the states, however, there is consensus for certain childhood immunizations. As a result, over the past 10-18 years, 97-98% of children in the United States are fully vaccinated against 6 diseases before starting school. 

Hepatitis B   (HBV) 

 

1992:  CDC recommends routine HBV vaccination for infants and mandatory HBV vaccination for children prior to enrolling in school or attending daycare in the US.

 

1995:  immunization recommendations updated to include catch-up for children ages 11-12 years.

 

1999:  immunization recommendations expanded to include catch-up for children <19 years, thus those born before 1980-1982 are probably unvaccinated.

Chickenpox   (VZV) 

 

1995:  Chickenpox VZV vaccine, given as single dose at 12-15 months, is approved in United States for children age 12 months and older

 

2006:  VZV vaccine as a single dose proved to be ineffective for long-term protection, so a second dose, given at 4-6 years, was added*

 * it took 11 years to determine that two doses were needed to provide greater and longer-lasting protection

Shingles   (VZV) 

 

2006:  a single dose shingles VZV live-attenuated vaccine was approved for adults > 60 years.

 

2015: a booster dose was recommended  after research determines the single-dose live-attenuated shingle vaccine offers no protection after 8 years*

 

2017: the new shingles vaccine, a two-dose subunit VZV vaccine, became available in U.S. for adults >50 years

*it took 9 years to determine that two doses were needed to achieve effective immunity.

HBV immunity grey zone

for those born 1982-1992

Depending upon when HBV vaccine was mandatory in their home state, and whether HBV vaccination was administered for at-risk employment or military service, individuals born:

  • after 1991 are likely vaccinated for HBV

  • between 1982-1992, uncertain HBV immunity status due to the ten-year span of changes to CDC’s recommendations for childhood HBV

  • before 1980-1982, are unlikely vaccinated for HBV

Chickenpox VZV immunity grey zone for those born 1994-2002

Depending upon when VZV vaccine schedule changes were mandated in their home state, individuals born: 

  • between 1994-2000 only received one dose 

  • 2004 or later received two doses 

  • 2000-2002, probably did not receive a 2nd dose; therefore they may have incomplete or ineffective immunity for VZV

Shingles VZV immunity

grey zone for adults who were vaccinated in 2006-2017

Variation in immunity, susceptibility, and/or severity of symptoms may depend upon whether the individual received:

  • live-attenuated, single dose

  • live-attenuated, single dose plus booster vaccine within 5-7 years of the initial dose subunit vaccine

  • two doses within 2-4 months

Correlating Vaccination History with Age-Related COVID-19 Observations

Since 1991, significant changes to were made to the childhood immunization schedule for HBV and VZV, which affects those born 1982-1992 and 1994-2002, respectively. However, the mandatory vaccine schedule has not changed in nearly 14 years, which may explain why children ages 1 to 12 or 14 years seem to be the most resistant to COVID-19.

Considering two sub-populations of adults who have more exposure to CoVid-19 than the average individual, healthcare workers and adults who cohabitated (sleeping together, sharing same bathroom and kitchen, etc) with a person who became ill with CoVid-19, some cases standout as being resistant to COVID-19. Limited sampling of these adults reveals a medical history of receiving vaccinations for both shingles (two-dose version) and hepatitis B.

If vaccination history is considered, most likely the reason is for an individual’s resistance to COVID-19 is cross-reactive immunity due to previous immunization using specific  vaccine(s). 

 

As the principal determinant of viral infectivity, the envelope spike is the main target of neutralizing antibodies. To shield the virus from immune recognition, the virus enhances its envelope and spikes with glycans; specifically N-linked, O-linked and mucin-like O-linked glycans. For the three viruses reviewed here (SARS-CoV-2, HBV and VZV), mucin-like O-linked glycans are crucial for infectivity. Other notable viruses with O-linked mucin-like domains include ebola, zika virus, hepatitis C virus, herpes simplex virus-1, herpes simplex virus-2 and influenza A virus.

SARS-CoV-2 

 

SARS-CoV-2 is an enveloped virus with spike (S) glycoproteins which project outwa rd from the virus envelope. The S protein has S1 and S2 subunits that are heavily glycosylated with N-Linked glycans, except at the S1/S1 junction, where there is a section of O-linked glycoproteins with a mucin-like domain (MLD).

 

Interestingly, for SARS-CoV of the SARS 2003 epidemic, the envelope spikes contain only N-linked glycans and there are no mucin-like O-glycans at its S1/S2 junction.

vaccine is pending

HBV 

 

HBV is an enveloped virus with spike-like protein complexes projecting outward. These envelope proteins are collectively known as hepatitis B surface antigen (HBsAg).

 

HBsAg is heavily glycosylated wtih N-linked glycans except at the pre-S2 domain projecting from the M surface protein where it contains a section of O-linked glycans containing a mucin-like domain (MLD).

the hepatitis B virus (HBV) subunit vaccine, is based on a single component of the viral envelope containing multiple MLD stretches

immunity requires

three vaccinations

VZV 

 

VZV is an enveloped virus with distinctive spikes composed of glycans. Glycoprotein E (gE) is the most abundant glycan of the VZV envelope. The structural organization of VZV gE is key to it’s infectivity and virulence:  VZV gE has two N-glycosylation sites joined by O-linked glycans with a mucin-like domain (MLD).

live-attenuated vaccine

immunity requires two vaccinations

a subunit vaccine, which is based on one single viral glycoprotein, gE, containing mucin-like O-linked glycans

immunity requires three vaccinations

Virus Structure Similarities

     

 The envelope structure of SARS CoV-2, HBV, and VZV have the following in common: 

  • spike-like projections extending outward from the viral envelope

  • areas of O-linked glycans amid N-linked glycans

  • mucin-like domains (MLD) domains associated with O-linked glycans

Vaccine Design Similarities

     

Vaccines for HBV and VZV have the following in common: 

  • each vaccine is a subunit vaccine

  • each vaccine uses a subunit of the viral envelope that contains O-linked glycans with mucin-like domains

  • each requires > 1 vaccination to confer immunity

Cross-reactive immunity triggers immune response when different antigens appear similar to the immune system. The clinical result is either a complete immune response and no disease, or a milder course of disease. It is quite possible that VZV alone or VZV + HBV vaccinations are providing cross-reactive immunity. If VZV +/- HBV immunization is providing cross-reactive immunity, then those persons who were properly vaccinated for VZV +/- HBV would seem resistant to COVID-19 or experience a milder course of disease.  Whereas those who received only one dose of VZV vaccine would be expected to experience a clinical course similar to unvaccinated individuals matched for age, health status and comorbidity. Until researchers consider the individual’s vaccination history, it is difficult to know whether HBV vaccination is providing additional or synergistic cross-immunity.

Discussion and Conclusion

Smallpox was a devastating disease that plagued the world for nearly 3,000 years. Efforts to control the disease were either fruitless or detrimental, until Edward Jenner used cowpox antigen to immunize people for smallpox.  Almost two hundred years later, after 25 years of world-wide effort for smallpox vaccination, smallpox was eradicated in the western hemisphere. 

 

There is significant antigenic commonality between the viruses SARS-CoV-2, HBV, ZVZ, and the HBV and VZV vaccines - a similar situation of cross-reactive immunity may be the pivotal factor in controlling the COVID-19 pandemic. Cross-reactive immunity due to prior immunization against VZV and/or HBV may be providing protection against SARS-CoV-2. The VZV and HBV vaccination history of children and some adults seems to correlate with the observed age-related disparity of SARS-CoV-2 infection rates and severity of COVID-19 symptoms.

 

Pandemics pose a great threat to public health and can affect economic stability worldwide. With an estimated 300-500 million deaths during the 20th century, smallpox was one of the most deadliest diseases. The control and eradication of smallpox is proof that, with effective vaccine design and collaborative effort, vaccination programs can be very successful. A vaccine for COVID-19 is imminent, but due to logistics of vaccine research and mass-production, the initial supply of CoV2 vaccines will be limited thus appropriated for those most at risk. Compounding matters is determine a vaccine’s success: as with other vaccines, it will take 5-10 years to determine the true efficacy of a COVID-19 vaccine. As the rate of SARS-CoV-2 infection increases exponentially, the number of persons infected with SARS-COV-2 will be staggering before it is known whether a 2nd or 3rd dose is needed to confer appropriate immunity.

Acquired Cross-Immunity Theory

       

The suggestion is to use VZV +/- HBV vaccination as a stopgap measure control COVID-19 until an effective vaccine is established or before SARS-CoV-2 undergoes antigenic drift and shift. By using VZV +/- HBV vaccination to activate/enhance cross-reactive neutralizing antibodies against SARS-CoV-2, we might quickly create protection against infection and mitigate the symptomatology, morbidity and mortality of COVID-19, until a SARS-CoV-2 vaccine is proven effective.

… either way, this is a win-win solution. 

 

Donation of any amount  from individuals, corporations, and foundations help support this investigation and fund upcoming research on autism, ADD, anxiety, Parkinson's disease, restless leg syndrome, Alzheimer's disease, and addiction.

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Lisa M. Avery, MD
 Neurologist
Clearwater, FL