1 May 2022 Episode 259 Some background on Adenoviruses, immunity and potential hepto-pathogenicity

Sun, 05/01/2022 - 17:44

Dear colleagues,

One of you asked the question what the relation could be between the new Adeno hepatitis in children and Adeno-specific T and B immunity.  A good point that inspired me to dig into the literature….

Ep 259-1: An “historic” paper by d’ Ambrosio 1982 in J. Hyg. Camb. They use already type-specific micro-neutralization tests for 33 different Adenoviruses and  focused on the evolution in children. Not surprisingly, neut Ab against the more common serotypes (with lower numbers) was higher than for the more recently discovered Adeno’s with higher numbers.  (Serotypes 41 apparently was not yet discovered at that time, but later it turned out to be more frequent than some Adeno’s with a lower number – see below.)

 

As could be expected, seroprevalence rose with age.  

 

And the serotypes with high numbers often remained negative even in teenagers and young adults.

Ep 259-2: A much more recent paper by Fausther in 2014 summarizes the human immune responses to Adenoviruses that can interfere with their use as vectors in vaccine development.  They stress that neutralizing Ab responses are highly serotype-specific, because they are mostly oriented towards the hyper-variable region (HVR) of the hexon protein, whereas T cell responses are able to recognize a broad range of serotypes, because they predominantly recognize conserved epitopes in the C-terminal part of the hexon protein.

 

 

 

Ep 259-3: Benjamin Lee Curr Op Infect Dis 2020 reviews pediatric acute gastroenteritis due to adenovirus 40/41 in low- and middle-income countries.

 

  • Gastroenteritis due to adeno 40/41 causes a substantial and under-appreciated burden of pediatric diarrheal disease in low- and middle-income countries, particularly in south Asia.
  • The epidemiology of adenovirus 40/41 GE remains poorly characterized due to the need for long-term prospective studies using type-specific molecular detection.
  • The role of other non-40/41 adenovirus types as etiologic agents of pediatric gastroenteritis remains unclear and requires further investigation.  

 

The term “hepatitis” does not occur in the text.

 

Ep 259-4: Wei-Xiong Yang Vaccine 2016: prevalence of Neut Ab in children against Ad 5 and Ad 41 in and around Xining City.

 

 

For both Adeno 5 and Ad 41 age dependent increase and clearly higher titers in village > town > city.   

Remarkably high titers for Adeno 41.

 

Ep 259-5: Shimizu 2007 outbreak of acute gastro-enteritis in children in Japan (high income country).

 

Adeno = second most etiology of viral GE in Maizuru city 2004-2005

 

 

Most Adeno are 41 and it comes in 2 subtypes

 

 

 

Ep 259-6: Ronan (2013) reviews fulminant hepatitis due to Adenoviruses

  • 89 cases are reviewed, more than half in children, most in immune compromised subjects

 

  • Symptoms mostly atypical (jaundice in 10 %, diarrhea in 12 %). Histology necrosis and intracellular inclusions (positive for Adeno)

 

  • Serotypes 5 (50%) and 2 (20 %). Serotype 41 not mentioned.

Ep 257-1:  Technical briefing from UK on novel form of hepatitis.

Very remarkable observations:

  1. Adenoviruses in feces almost disappeared in children during COVID period (Aril 2020-Sept 2021) and suddenly re-appear from Oct 2021 on.

 

 

  1. At the same time (Oct 2022) suddenly much more  Adeno infections around the time of SARS-CoV-2 infection in children

 

  1.  In hepatitis cases, Adeno 41 is clearly the most frequently detected virus

 

 

CONCLUSIONS

  1. Adeno 41 is known as a frequent cause of diarrhea in young children in low/middle, but also high income countries.  Seroprevalence increases rather rapidly with age and more so in less hygienic conditions. 
  2. Adeno-associated hepatitis was only known to occur in immune suppressed children and adults.
  3. Adeno 41 has not been associated with hepatitis before, but it seems a very likely cause in the recent epidemic in children.
  4. Humoral immunity to Adeno is very sero-type specific, while T cell immunity is cross-reactive.  
  5. The exposure of young children to GE adenovirus infection was very low during the COVID period (April 2020 -Sept 2021).  

How to make sense out of these observations?

A potentially more hepatotropic 41 sub-type has arisen and starts to infect children, which lack specific antibodies, but do have some broader T cell immunity.  This condition allows the virus to infect hepatocytes, proliferate and spread in the liver, because of no neut Ab present. Meanwhile cross-reactive memory T cells are activated (which takes a few days) and those attack the infected liver cells, with serious hepatocellular damage.   

Older children and adults may have a better “Adeno-memory”, because of multiple encounters before the COVID era. Therefore they may have more serotype 41-specific Ab and cross-reactive T cells, which are easily activated to prevent this pathologic scenario.  They may quickly eliminate the new virus, without any liver-related symptom (while other GE symptoms may still occur?) or they may only present a subtle and self-limiting hepatitis that remains subclinical and therefore has not been reported.  

Note:

It is quite evident that both Ab and T cells have a role in protection against Adenoviral infection, but I could not find data on the duration of this protection

Ep 258-7: Kalu in Pediatr Infect Dis J 2010 suggests that in nasopharyngeal secretion the same serotype (but sometimes a different strain) can be found in case of repeated respiratory infection.

Ep 258-8: Nishio in Microbiol Immunol 1992 performed an extensive follow up of 7 children for gastro-enteral Adenoviral infections (22 person years) and identified repeated infections with different serotypes, but never with the same one.  

Since Adeno infections are so common also in adults, it is still possible that one needs repeated exposure to Adeno 41 for instance to maintain a certain level of protection.  Therefore it is possible that “interrupted exposure” during the COVID period 2020-2021 may explain a weakened protection (with ensuing increased pathogenicity), especially in children who had no or limited exposure to Ad 41 before.  But, to be honest, there is no proof in the literature.

 

I’m curious to read your reactions

Best wishes,

Guido

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