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Original antigenic sin in dengue - Hoskins effect


1 Department of Medicine, MVJ Medical College and Research Hospital, Bengaluru, Karnataka, India
2 Department of Medicine, MVJ Medical College and Research Institution, Bengaluru, Karnataka, India

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Date of Submission15-Sep-2021
Date of Decision16-Oct-2021
Date of Acceptance18-Oct-2021
Date of Web Publication02-Mar-2022
 

  Abstract 


Dengue is a mosquito-borne viral infection found in tropical and subtropical climates worldwide, mostly in urban and semiurban areas. The virus responsible for causing dengue is called dengue virus. There are four dengue virus serotypes, implying that it is possible to be infected four times. While many dengue virus infections produce only mild illness, occasionally, this develops into potentially lethal complications, called severe dengue, dengue hemorrhagic fever, and dengue shock syndrome. Currently, there is no specific treatment for dengue/severe dengue. Due to a rise in mortality rates associated with dengue hemorrhagic fever, severe dengue, and dengue shock syndrome, a better understanding of the reason behind dengue hemorrhagic fever is required. Hence, in this article, we further describe the original antigenic sin in dengue and how the occurrence of Hoskins effect is a major determinant factor for the progression to dengue hemorrhagic fever.

Keywords: Antigenic, dengue, hemorrhagic


How to cite this URL:
Kamath V, Olakkengil ND. Original antigenic sin in dengue - Hoskins effect. APIK J Int Med [Epub ahead of print] [cited 2022 Oct 6]. Available from: https://www.ajim.in/preprintarticle.asp?id=338909





  Introduction Top


Dengue is a mosquito-borne viral disease that has rapidly spread in all regions of the WHO in recent years. Dengue virus is transmitted by female mosquitoes mainly of the species Aedes aegypti and, to a lesser extent, Aedes albopictus. These mosquitoes are also vectors of chikungunya, yellow fever, and Zika viruses. Dengue is widespread throughout the tropics, with local variations in risk influenced by rainfall, temperature, relative humidity, and unplanned rapid urbanization.[1],[2]

Dengue is caused by a virus of the Flaviviridae family, and there are four distinct, but closely related, serotypes of the virus that cause dengue (DENV-1, DENV-2, DENV-3, and DENV-4). Recovery from infection is believed to provide lifelong immunity against that serotype.[3] However, cross-immunity to the other serotypes after recovery is only partial and temporary. Subsequent infections (secondary infection) by other serotypes increase the risk of developing severe dengue.[4]

The spectrum of Dengue can range from subclinical disease (people may not know they are even infected) to severe flu-like symptoms in those infected. Although less common, some people develop severe dengue, which can be any number of complications associated with severe bleeding, organ impairment, and/or plasma leakage.[5] Severe dengue has a higher risk of death when not managed appropriately. Severe dengue was first recognized in the 1950s during dengue epidemics in the Philippines and Thailand. Today, severe dengue affects most Asian and Latin American countries and has become a leading cause of hospitalization and death among children and adults in these regions.[6]


  Global Burden of Dengue Top


The incidence of dengue has grown dramatically around the world in recent decades. A vast majority of cases are asymptomatic or mild and self-managed, and hence, the actual numbers of dengue cases are under-reported. Many cases are also misdiagnosed as other febrile illnesses.[7]

The number of dengue cases reported to the WHO increased over 8-fold over the last two decades, from 505,430 cases in 2000, to over 2.4 million in 2010, and 5.2 million in 2019. Reported deaths between 2000 and 2015 increased from 960 to 4032.


  Distribution and Outbreaks of Dengue Top


Before 1970, only nine countries had experienced severe dengue epidemics. The disease is now endemic in more than 100 countries in the WHO regions of Africa, the Americas, the Eastern Mediterranean, South-East Asia, and the Western Pacific. America, South-East Asia, and Western Pacific regions are the most seriously affected, with Asia representing ~70% of the global burden of disease.[8]

Not only is the number of cases increasing as the disease spreads to new areas, including Europe, but explosive outbreaks are also occurring. The threat of a possible outbreak of dengue now exists in Europe; local transmission was reported for the first time in France and Croatia in 2010, and imported cases were detected in three other European countries.[9] In 2012, an outbreak of dengue on the Madeira Islands of Portugal resulted in over 2000 cases, and imported cases were detected in Mainland Portugal and 10 other countries in Europe. Among travelers returning from low- and middle-income countries, dengue is the second most diagnosed cause of fever after malaria.[8],[9]

In 2020, dengue affected several countries, with increased number of cases in Bangladesh, Brazil, Cook Islands, Ecuador, India, Indonesia, Maldives, Mauritania, Mayotte (Fr), Nepal, Singapore, Sri Lanka, Sudan, Thailand, Timor-Leste and Yemen. In 2021, 1 075 834 cases have been reported, the majority from Brazil (752 284), Vietnam (43 028), Peru (35 728), Philippines (32 555) and Réunion (29 333). Since the previous update, week 30, 124 413 new cases have been reported, the majority from Brazil (80 552), India (7 207), Nicaragua (5 702), Vietnam (5 608), and Bangladesh (5 535). (Statistics as per European centre for disease prevention and control).[10]

Transmission

Mosquito-to-human transmission: The virus is transmitted to humans through the bites of infected female mosquitoes, primarily the Aedes aegypti mosquito. Other species within the Aedes genus can also act as vectors, but their contribution is secondary to Aedes aegypti.[11]


  What is the Original Antigenic Sin? Top


Original antigenic sin (OAS), also known as antigenic imprinting or the Hoskins effect, refers to the tendency of the body's immune system to favor the utilization of immunological memory based on a previous infection when a second slightly different version of that foreign pathogen (e.g., a virus or bacterium) is encountered.[11] Original antigenic sin is also known as Hoskins effect. It was named after professor Hoskins and his colleagues who first described the event in a publication in the lancet journal in the year 1970. It was titled 'The Hoskins Paradox' and it described how annually repeated influenza vaccination would not confer lifelong immunity against influenza,[12] This leaves the immune system “trapped” by the first response it has made to each antigen and unable to mount potentially more effective responses during subsequent infections. Antibodies or T-cells induced during infections with the first variant of the pathogen are subject to a form of OAS, termed repertoire freeze.[13]

The phenomenon of OAS has been described in relation to influenza virus, dengue fever, human immunodeficiency virus, and to several other viruses.

This phenomenon was first described in 1960 by Thomas Francis Jr., in the article “On the Doctrine of Original Antigenic Sin.” It is named by analogy to the theological concept of original sin.[14] The term “original antigenic sin” was coined by Thomas Francis Jr. in the late 1960s to describe patterns of antibody response to influenza vaccination.[15] Francis' father was a Presbyterian minister, likely a reason why he used a theologically charged term to describe a biologic phenomenon.The original sin was coined in reference to biblical times when Adam and Eve, the first of the race disobeyed GOD and was thrown out of the garden of Eden.[16] Thus inflicting the original sin to all generations that followed and which could only be cleansed once baptized and which was then later still passed on from generation to generation. Similarly, in dengue, the OAS describes how a person affected at least only once by dengue is susceptible to dengue hemorrhagic fever.

Furthermore, the concept was recently summarized as “first flu is forever,” indicating the continued relevance of OAS throughout life. The authors of this perspective commented on the observation that the first infection in life may predetermine later protection from encounters with avian influenza viruses.[17] This is exactly the idea that Francis et al. were describing in terms of antibodies 60 years ago.

The immune response to the first infection imprinted itself on subsequent responses to infections and particularly vaccination. The doctrine was based on age cohort-associated antibody patterns observed in the sera collected from the community, as well as on differences in antibody responses to vaccination between children and adults. The result could be either positive or negative and could be corrected by vaccination with appropriate antigens, termed the “blessing of induced immunity.”[18]

The concept of OAS was developed first on the basis of detection of residual antibodies from earlier infection with these strains and then by the use of experimental vaccination with monovalent vaccines containing these inactivated viruses.[19]


  In B-Cells Top


During primary infection, long-lived memory B-cells are generated, which remain in the body, and provide protection from subsequent infections. These memory B cells respond to specific epitopes on the surface of viral proteins in order to produce antigen-specific antibodies, and are able to respond to infection much faster than naïve B cells. This effect shortens the amount of time required to clear subsequent infections.[19]

Between primary and secondary infections, or following vaccination, a virus may undergo antigenic drift, in which the viral surface proteins (the epitopes) are altered through natural mutation, allowing the virus to escape the immune system.[20]

When this happens, the altered virus preferentially reactivates previously activated high-affinity memory B-cells and spurs antibody production. However, the antibodies produced by these B-cells generally ineffectively bind to the altered epitopes.[21] In addition, these antibodies inhibit the activation of higher affinity naive B-cells that would be able to make more effective antibodies to the second virus. This leads to a less effective immune response, and thus, recurrent infections may take longer to be cleared.[22]


  In T-Cells Top


A similar phenomenon has been described in cytotoxic T-cells (CTL). It has been demonstrated that during a second infection by a different strain of dengue virus, the CTLs prefer to release cytokines instead of causing cell lysis.[23] As a result, the production of these cytokines is thought to increase vascular permeability and exacerbate damage to endothelial cells, a phenomenon known as dengue hemorrhagic fever.[24]

OAS is of particular importance in the application of vaccines. In dengue fever, the effect of OAS has important implications for vaccine development. Once a response against a dengue virus serotype has been established, it is unlikely that vaccination against a second will be effective, implying that balanced responses against all four virus serotypes have to be established with the first vaccine dose.[25]


  Conclusion Top


Despite the constant implication of “sin” as a negative entity, it is clear that OAS-like responses are neither inherently “good” nor “bad.” The desirability of OAS responses is instead situation-dependent. An abundance of terminology has evolved to describe OAS-like phenomena, all of which vary minutely in the presumptive consequence (positive, negative, agnostic) of these responses. Selective elicitation of OAS may be beneficial for the induction of broad immunity against conserved epitopes, for which there is pre-existing immunity and would also help in the future for the development of vaccines.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. The global distribution and burden of dengue. Nature. (2013) 496:50a4-7.   Back to cited text no. 1
    
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3.
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4.
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7.
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8.
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9.
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10.
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11.
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12.
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13.
Thomas Francis Jr. “On the doctrine of original antigenic sin”. Proceedings of the American Philosophical Society. 1960;104:572–578.  Back to cited text no. 13
    
14.
McMichael AJ. “The original sin of killer T cells”. Nature. 1998;394 (6692):421–422.  Back to cited text no. 14
    
15.
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16.
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18.
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19.
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20.
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21.
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22.
Mangada MM, Endy TP, Nisalak A, Chunsuttiwat S, Vaughn DW, Libraty DH, et al. Dengue-specific T cell responses in peripheral blood mononuclear cells obtained prior to secondary dengue virus infections in Thai schoolchildren. J. Infect. Dis. 2002;185:1697-1703.  Back to cited text no. 22
    
23.
Hatch S, Endy TP, Thomas S, Mathew A, Potts J, Pazoles P, et al. Intracellular cytokine production by dengue virus-specific T cells correlates with subclinical secondary infection. J. Infect. Dis. 2011;203:1282–1291.  Back to cited text no. 23
    
24.
Gunther VJ, Putnak R, Eckels KH, Mammen MP, Scherer JM, Lyons A, et al. A human challenge model for dengue infection reveals a possible protective role for sustained interferon γ levels during the acute phase of illness. Vaccine 2011;29:3895-3904.   Back to cited text no. 24
    
25.
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Correspondence Address:
Vasantha Kamath,
Department of Medicine, MVJ Medical College and Research Hospital, Hoskote, Bengaluru Rural - 562 114, Karnataka
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajim.ajim_96_21





 

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    -  Kamath V
    -  Olakkengil ND


Abstract
Introduction
Global Burden of...
Distribution and...
What is the Orig...
In B-Cells
In T-Cells
Conclusion
References

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