Evidence for Increased Immune Protection against Sars-CoV-2 from Exposure to BCoVs

Mostly written in April 2020, updates on todo since outdated and sometimes wrong. Not all references correctly linked as of 24.3.21

explorative section

Content

• Content
• Summary
• Relevance
  • Epidemiological
  • Medications
• Evidence from Distribution of Covid-19
  • Covid-19 in Switzerland
  • Covid-19 in Spain
  • Remark
  • Observed Interspecies Jumps
• Mechanisms of Crossprotection
  • Current Guesses
  • Previous Guesses of Mechanisms likely False
  • Biological Evidence
• Next Steps
• References

Summary

While there are possible explanations for many epidemiological observations of the Sars-2 strains, causing Covid-19, spread in the first months of 2020: spread mainly in absolutely dry and cold air and less spread in warm and humid air. Thus increased spread with increasing latitudes and away from coastal areas. Because cold and dry air likely increases both the airborne transmission and decreases the mucus clearance. Air pollution (decreased mucus clearance) and increased public transport (increased spread) could contribute to the preference for cities of Sars-CoV-2. However some regional patterns fall through these reasons:

• in Switzerland not only the highest prevalence in severe cases (mild and moderate cases were not admitted to testing and thus not recorded in February/March/April 2020) but also the highest death rates are observed in Geneva (GE) and Ticino (TI), areas which have few cattle farming. On the other hand areas, where cattle farming is widespread across the entire area, seem to have an increased resistance: only a couple of deaths and few cases are recorded in the cantons LU, AI, AR, OW, UW, AG, TG.
• Spain: In communities where cattle farming is common (Galicia, Basque Country and La Rioja)[to be confirmed], the death rate is lower and the recovery rate higher than in Central Spain.
• Across the world no Covid-19 hot-spot with many severe cases has been observed in regions with a lot of cattle farming. Tehran, Wuhan, Madrid, Milan and New York are not known as cattle farming regions.

A possible explanation is that in cattle farming areas bovine coronavirus (BCoV) are transmitted to humans such that the immune system is trained to fight Betacoronaviruses. Transmissions and the induced build up of some form of resistance could occur regularly or just once as an infant and possibly yield lifelong increased protection. Such an immune protection could explain why some people notice no or only few symptoms. Noteworthy some seniors remain mostly asymptomatic and other seniors experience severe or even fatal Covid-19.

Coronavirus infections in humans can elicit immune protection (more precisely no additional serum conversion is observed) to other coronaviruses Van der Hoek et al.:

• OC43 =protects=> HKU1 (only unidirectional)
• NL63 =protects=> 229E (only unidirectional)

A bovine coronavirus strain, namely HECV-4408, was isolated from a child from a rural area in Texas suffering diarrhea Zhang et al.

If a cross protection between BCoVs and Sars-CoV-2 exists and if yes how it works remains to be determined. Depending on the mechanism of action it could be used in many ways.

Relevance

The relevance depends on the mechanisms of crossprotection and how much protection is provided. Possible use cases are polyvalent:

Epidemiological

• knowing that people have an increased immune protections and therefore experience only mild symptoms and possibly have reduced spreading of Sars-CoV-2 is relevant to manage the current Covid-19 pandemic.
• Serum conversion occurrences: It could be that a different or no seroconversion occurs to people previously exposed to different strains of Betacoronaviruses.

Medications

Knowledge of cross immune reactions can help to develop medications and even literal vaccines are thinkable vice versa.

• increase the immune response against Sars-CoV-2 or even provide paths for full immunization
• even a literal vaccine is thinkable (the long-term pathogenesis of BCoVs needs to be reevaluated first)
• Sars-CoV-2 infections could protect against OC43 or other BCoV infections, which could be more harmful in the long run than Sars-CoV-2

Evidence from Distribution of Covid-19

In the following the in country distribution of Covid-19 is described. Since inside countries the testing schemes tend to be more or less uniform (data specifications). Namely the data Switzerland and Spain are used , two countries in which only severe Covid-19 cases have been recorded.

Covid-19 in Switzerland

The following analysis is for the months March and April 2020. In this period only severe Covid-19 cases were tested. Mild and moderate cases were not admitted to testing and thus not recorded in February/March/April 2020.

Incidence rates of both cases and deaths varies a lot between the different regions (Cantons which correspond to states).

• Prevalent Cattle Farming: In areas where cattle farming is prevalent (AG, LU, AI, SG, FR, NE, ZH, VS, BE, FR, JU etc.), the number of deaths per 100K is about 6 in median and 8 in average (March and April 2020).

• Few Cattle Farming: In areas where cattle farming is less common the average number of deaths per 100K is about is about 30 in average and 32 in median [more accurate statistics on todo]. Cantons with few cattle farming:

  • GE is a city canton and surrounded by Lac Lemon and France (less subventions there).
  • BS is a city canton which has a long urban and trade tradition. In the south there are some forested hills, and in the west France and North-East is Germany.
  • TI has a few cattle farming but mostly close to the mountains and away from the cities. The largest city Lugano is surrounded by the Lago di Lugano and forests.
  • VD has cattle farming but majority of the population lives on northern cost of the Lac Lemon, where the largest city Lausanne is located. Lausanne has mainly vineyards and forests to the North and Lac Lemon in the South.

The observation holds when considering only cantons with large cities or when considering only uniform language regions. Areas with a lot of cattle farming have lower death rates (both positive tested cases and deaths per capita):

• Urbanized Areas: ZH, ZG have a lower rates GE, BS
• French Speaking Region: JU, FR, NE and VS have lower rates both per severe cases and per population than GE and VD.
• German Speaking Region: TG, AI, SG, LU, AG have lower rates than BS.

Remark: Cattle farming is very common in many areas in Switzerland due to a long tradition and an accompanying tradition of making a variety of tasty cheeses. Care has been taken to preserve traditional recipes and the microbes used, throughout the industrialization of agriculture in the 20th century. Additionally the market for milk and meat is protected and significantly subsidized. The support is higher than for other forms of agriculture.

Subjective Remark: I consider distributed agriculture as important and worth preserving. Both subsidies and protected markets are suitable means to support desired industries whether worth preserving or giving space to develop. Economy solely on global effectiveness trimmed, yields that. But often only that. Question is, in which situations this is wanted.

Covid-19 in Spain

The cattle rich regions in the North and North East: Galicia, La Rioja, Basque Country have a lower death rate and higher recover rate than Madrid, Valencia, Castile, Catalonia and Leon. As expected from the humid climate in the communities Canary Islands, Melila and Balearic Islands the recover rates are high and the death rates are low compared to central Spain.

Remark

Similar patterns are possibly in the USA and France. For analysis, ideally the partitioning of population is fine-grained, at most a few 100K people per partition.

Observed Interspecies Jumps

There are many examples where BCoVs jumped species borders, for which at least interspecies infection is necessary but likely many occur until one yields a species jump. Frequent enteric coronavirus infections to humans occur(ed) likely, but they are not easy to prove [citation coming]. Examples where they have PCR confirmed:

• The HECV-4408 coronavirus was isolated from a child having diarrhea in 1994 as described in Zhang et al Examples of a successful jump from BCoV between humans and bovine:
• OC43 likely was a BCoV jump to humans.

Mechanisms of Crossprotection

Current Guesses

Local T cells distributed through the respiratory tract recognize viral infections and induce cell death to prevent viral replication [argumentation 22.10. on todo-list].

• recognizing conserved parts the spikes or the N protein
• T cells recognizing more general anomalies of virus infected cells [in work]

Previous Guesses of Mechanisms likely False

Adaption of Macrophages

Epigenetic adaption of alveolar macrophages netea, xing // Macrophages likely don’t help to fight coronavirus infections.

Biological Evidence

Antibodies

Antibodies against some well preserved parts of proteins.

• some extern proteins, which are preserved. The antibodies could either render the viruses noninfectious or acting as opsonin. Candidates:
  • S1
• non extern proteins presented via MHC 1. The antibodies act as opsonin or are directly receptors of cytotoxic cells.
  • N First observations of cross immune protections are described. Then examples of host species jumps of betacoronaviruses are described including jumps from BCoV to humans.

Cross Immune Protections between different Coronaviruses

Cross immune protections against coronaviruses have been observed for different strains, therefore cross protections can exists for coronaviruses. Examples of observed cross immune protections are:

• Van der Hoek et al. observed by analyzing serum conversions (no additional serum conversion occurs):
  • OC43 -protects-> HKU1 (only unidirectional)
  • NL63 -protects-> 229E (only unidirectional)
• Han et al showed that calves inoculated with HECV-4408get cross-protective immunity against the strain BCoV DB2. HECV-4408 is a strain that has been observed to cause acute diarrhoea in humans, see human bcov infections

Next Steps

• Analyse spread patterns in other countries: USA, France, … // The spread is different in rural areas and cities e.g. due to cleaner air and/or less dense living conditions e.g. less residential blocks (Spread Analyses).
• Widespread serology for HCoVs and statistics if there’s a relation to pathogenesis of Covid-19.
• Analyse birthplace and grow up locations of Covid-19 patients (e.g. from the cruise ships).
• figuring out whether BCoVs genetically cross/combine with other HCoVs. // to check how frequent recombination between different different coronaviruses species and between different types and with other viruses/hosts are (the He gene is likely influenza acquired [to cite])

References

• vanderhoek2012

  Dijkman, R., Jebbink, M. F., Gaunt, E., Rossen, J. W., Templeton, K. E., Kuijpers, T. W., & van der Hoek, L. (2012). The dominance of human coronavirus OC43 and NL63 infections in infants. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology, 53(2), 135–139. https://doi.org/10.1016/j.jcv.2011.11.011

• borucki

  Borucki, M. K., Allen, J. E., Chen-Harris, H., Zemla, A., Vanier, G., Mabery, S., Torres, C., Hullinger, P., & Slezak, T. (2013). The role of viral population diversity in adaptation of bovine coronavirus to new host environments. PloS one, 8(1), e52752. https://doi.org/10.1371/journal.pone.0052752

• woo

  Woo, P. C., Lau, S. K., Huang, Y., Yuen, K. Y. (2009). Coronavirus diversity, phylogeny and interspecies jumping. Experimental biology and medicine (Maywood, N.J.), 234(10), 1117–1127. https://doi.org/10.3181/0903-MR-94

• Zhang 94

  Zhang, X.M., Herbst, W., Kousoulas, K.G. and Storz, J. (1994), Biological and genetic characterization of a hemagglutinating coronavirus isolated from a diarrhoeic child. J. Med. Virol., 44: 152-161. https://doi.org/10.1002/jmv.1890440207