Chikungunya Fever A Review Of The Literature Biology Essay

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The Newala and Masasi Districts of the Southern Province, Tanzania, reported its first dengue-like outbreak in 1952-1953, on the basis that this epidemic involved debilitating joint pains and shorter incubation period, thereby excluding dengue (Robinson 1955). The infection was called chikungunya; a word from the Makonde dialect describing patient's contorted posture (Lumsden 1955). Chikungunya is an arthropod borne virus (arbovirus) of the genus: Alphavirus from Togaviridae family. It is transmitted to humans mainly by the day biting mosquito species Aedes aegypti and Aedes albopictus (Townson and Nathan 2008). Moreover, Aedes aegypti eggs collected from the Tanzanian outbreak were used for the first isolation of Chikungunya virus (CHIKV) (Ross 1956). CHIKV contains a positive-sense single stranded RNA genome, enclosed in an icosahedral nucleocapsid, all enclosed in a phospholipid bilayer envelope. Embedded in the envelope are multiple copies of two encoded glycoproteins E1 and E2, a small glycoprotein E3, and a hydrophobic peptide 6K (Strauss and Strauss 1994). However, the roles of these glycoproteins are not elucidated, but it can be assumed that it could facilitate the attachment of the virus to host cell.

History

Subsequent to the Tanzanian epidemic, several outbreaks have been reported worldwide, including the Indian Ocean Islands; La Reunion (Renault et al. 2007), Mayotte (Sissoko et al. 2008), and the Maldives (Yoosuf et al. 2008). There were outbreaks whereby Chikungunya had concurrence with other infections; with Dengue (Ratsitorahina et al. 2008, Yoosuf et al. 2008) and with Plasmodium falciparum infection (Pastorino et al. 2004). Moreover, Chikungunya have been imported into several European countries; United Kingdom (HPA 2007), France (Hochedez et al. 2007), Germany, Switzerland, Denmark, Poland (Panning et al. 2008), with Italy witnessing its first CHIKV outbreak in 2007 (Rezza et al. 2007).

Aim of review

The Italian outbreak has demonstrated that only one viraemic person was required to instigate an outbreak and due to increased population movement worldwide, CHIKV could extend to pandemic proportions (Rezza et al. 2007). Furthermore, the outbreaks could have been underestimated due to its concurrence with other infections. Thus, this literature review will demonstrate to the reader that the Western medicine should be planning for CHIKV outbreaks which are becoming increasingly possible due to world climate change.

Clinical Features

Chikungunya is a mild and self limiting infection (Rezza et al. 2007) with incubation period of 2-7 days (Robinson 1955). Patients usually presents with a number of clinical features, with fever, fatigue, joint pain, anorexia, and nausea presenting as common clinical features (Table 1). Arthalgia and myalgia mainly involves the extremities of wrists, ankles, hands, feet and phalanges, while skin rash and petechiae are manifestations of haemorrhage (Kannan et al. 2009). During the La Reunion outbreak, Géraldin et al. (2008) observed vertical transmissions from mother to child, with newborns presenting with chikungunya infection without prior mosquito bites. These neonates became symptomatic between 3-7 days postpartum, with presentation of fever, pain, poor feeding, disseminated intravascular coagulation (DIC) with gastrointestinal and cerebral bleeding, petechiae, and distal joint oedema. Encephalitis, thrombocytopenia and haemorrhagic fever were presented as severe neonatal infections; however, no fatalities were reported (Gérardin et al. 2008).

Table 1. Average frequency of clinical features of chikungunya infection reported in the La Reunion, Indian, Maldive, Italian and Mayotte outbreak.

Clinical Features associated with Chikungunya

*Average Number of cases (%)

References

Most common

Fever

98.3

Kannan et al.2009, Renault et al.2007, Rezza et al.2007, Sissoko et al.2008, Yoosuf et al.2008.

Fatigue

93.0

Rezza et al.2007.

Joint pain

86.9

Renault et al.2007, Rezza et al.2007, Yoosuf et al.2008.

Anorexia

86.4

Kannan et al.2009.

Nausea

83.1

Kannan et al.2009.

Arthralgia

67.1

Kannan et al.2009, Sissoko et al.2008, Yoosuf et al.2008

Oedema

61.3

Kannan et al.2009

Headache

60.1

Kannan et al.2009, Renault et al.2007, Rezza et al.2007, Sissoko et al.2008, Yoosuf et al.2008

Myalgia

57.2

Kannan et al.2009, Yoosuf et al.2008

Muscle pain

53.8

Renault et al.2007, Rezza et al.2007

Skin rash

52.0

Rezza et al.2007

Itch/ Rash

42.4

Kannan et al.2009, Yoosuf et al.2008

Least common

Cutaneous eruptions

32.5

Renault et al.2007

Diarrhoea

23.0

Rezza et al.2007

Itching

20.0

Rezza et al.2007

Arthritis

19.0

Yoosuf et al.2008

Oral ulcer

17.8

Kannan et al.2009

Vomiting

15.0

Kannan et al.2009, Rezza et al.2007

Photophobia

15.0

Rezza et al.2007

Eye pain

11.6

Kannan et al.2009

Eye congestion

7.6

Kannan et al.2009

Sore throat

4.0

Yoosuf et al.2008

Conjunctivitis

3.0

Rezza et al.2007

Haemorrhage

1.4

Kannan et al.2009

*Key: the number of cases has been averaged.

Transmission of CHIKV

CHIKV requires two types of hosts to complete its replication cycle. Firstly, Aedes mosquito species transmits the virus to animals, and act as definitive hosts. Secondly, humans and other animals become infected with the virus and act as intermediate hosts. The transmission between the natural hosts (primates, birds, rodents and others) and the definitive hosts involves the sylvatic (main) cycle (Pardigon 2009). By disrupting this cycle, humans became incidental hosts, resulting in urban transmission cycles yielding epidemics. These humans could transmit CHIKV directly to domestic mosquitoes (Gould and Higgs 2009) and indirectly to domestic animals such as fowl, pigeons and goats (Lumsden 1955). When an Aedes mosquito ingests viraemic blood meal, CHIKV replicates in the salivary glands and ovaries, sites where it can be excreted. Upon another blood meal, the mosquito injects the viraemic saliva into a susceptible host. Contrary, within the ovaries, CHIKV is transmitted to the mosquitoes' eggs by vertical transmissions (Figure 1). The desiccated nature of these eggs enables it to survive longer periods in the environment, where they are hatched during the rainy season (Gould and Higgs 2009).

Figure 1. The overview of CHIKV's transmissions cycle in mosquito and human (Evenor 2010).

Aedes mosquito becomes infected after taking a blood meal from an infected intermediate host

Upon another blood meal, the Aedes mosquito injects viraemic saliva into a susceptible host

The viraemic blood travels to the gut, where CHIKV undergoes replication within the gut wall

The egg later developed into a mosquito infected with CHIKV

CHIKV travels to the ovaries, where it is transmitted to the mosquito's eggs by vertical transmission

The intermediate host becomes viraemic with presentation of clinical features

CHIKV penetrated the gut wall, where it is disseminated through the bloodstream

CHIKV travels to the salivary glands, where it undergoes replication

Distributions of Aedes albopictus and Aedes aegypti

Aedes aegypti was the predominant vector during earlier outbreaks in Africa (Lumsden 1955), and it has been implicated in some recent outbreaks in Africa (Gould et al. 2008) and Indonesia (Laras et al. 2005). However, Aedes albopictus have been described as the main vector implicated in a number of recent outbreaks, between 2005 to 2007 (Leroy et al. 2009, Pagès et al. 2009, Ratsitorahina et al. 2008, Renault et al. 2007, Sissoko et al. 2008). In the Gabonese outbreak involving both vectors, Vazeille et al. (2008) hypothesised that Aedes albopictus is a more suitable vector for CHIKV than Aedes aegypti, as it has a higher susceptibility for the virus. The two vectors have been recovered from several breeding sites with some overlap (Table 2). Tyres have been the main source of Aedes albopictus larval importation into Italy, in 1992, from Atlanta, USA. Consequently, the trade of these used tyres within Italy had caused large infestations of Aedes albopictus in Linguria, Veneto, Lombardy and Eimlia-Romagna regions, by the end of 1995 (Knudsen et al. 1996). Aedes aegypti larvae predominate inside home, whereas Aedes albopictus larvae predominate outside home (Preechaporn et al. 2006).

Table 2. The natural and artificial breeding sites for Aedes aegypti and Aedes albopictus larvae.

Natural and artificial breeding sites

Incidence of Aedes aegyptilarvae

Incidence of Aedes albopictus larvae

References

Barrels

X

-

Gould et al.2008

Drums

X

X

Gould et al.2008, Ratsitorahina et al.2008

Buckets

-

X

Ratsitorahina et al.2008

Flower pots

X

-

Gould et al.2008

Discarded cans

X

X

Preechaporn et al.2006, Ratsitorahina et al.2008

Coconut shells

-

X

Preechaporn et al.2006, Ratsitorahina et al.2008

Clay water jars

X

-

Gould et al.2008

Mango tree holes

X

-

Lumsden 1955

Wetlands

X

X

Vazeille et al.2008

Discarded tyres

X

X

Preechaporn et al.2006, Ratsitorahina et al.2008

Plant pots

X

X

Preechaporn et al.2006, Ratsitorahina et al.2008

Gardens

-

X

Adhami and Reiter 1998

Discarded plastic bottles

-

X

Adhami and Reiter 1998, Preechaporn et al.2006

Wet containers

-

X

Ratsitorahina et al.2008

Banana trees

X

-

Preechaporn et al.2006

Plant axils

-

X

Preechaporn et al.2006

Animal pans

X

X

Preechaporn et al.2006

Plastic containers

X

X

Preechaporn et al.2006

Cement tanks

X

X

Preechaporn et al.2006

Ant guards

X

-

Preechaporn et al.2006

Preserved areca jars

-

X

Preechaporn et al.2006

Small and large earthen jars

X

X

Preechaporn et al.2006

Key: (X):- present, (-):- absent.

Effect of climate change

Outbreaks have been associated with climatic conditions such as temperatures and high rainfall. Temperatures influence the developmental rate of Aedes albopictus larvae to adult mosquitoes, with the rate optimising at temperatures between 25 to 30oC (Straetemans 2008). Thus, Tilson et al. (2009) argued that mean monthly temperatures above 20oC are required to initiate an outbreak, as illustrated by the Italian outbreak that was initiated in June and subsided in September when the monthly average temperatures were 22oC and fell below 20oC. Mean annual rainfalls over 500mm is required (Straetemans 2008) to provide suitable breeding environment for the mosquitoes to expand their population (Lumsden 1955); as a result, most outbreaks have been associated with high rainfall (Lumsden 1955, Pastorino et al. 2004, Renault et al. 2007, Sissoko et al. 2008, Yoosuf et al. 2009) as illustrated in Table 3. In 2009, the UK Met office (2010) recorded a mean annual rainfall and temperature of 1201.3mm and 9.2oC, respectively. The rainfall is sufficient to initiate an outbreak; however, the low temperature is insufficient to support the mosquitoes' life cycle. Therefore, the question is what would the impact be to the UK if the climatic condition changes to favour this mosquito?

Table 3. Mean temperature and the amount of rainfall that were reported during several outbreaks.

Country

Duration of the outbreak

Mean monthly Temperature (oC)

Months mean monthly temperature were collected

Amount of Rainfall

(mm)

Months high rainfall were recorded

Reference

Tanzania

1952 - 1953

21.8 - 28.5

Jun - Nov

1203

Jan - Dec 1952

Lumsden 1955

Bogor

Aug - Dec 2001

24 - 26.2

Jan 2000 - Dec 2001

NA

Laras et al.2005

Bekasi

Jan 2002

26.2 - 29.6

Jan 2001 - Dec 2002

1931

Jan - Feb 2002

Laras et al.2005

Maldives

2006 - 2007

NA

NA

970

Nov - Dec 2006

Yoosuf et al.2009

Key: NA- not available

Distribution of Chikungunya outbreak

Mayotte (French Overseas Territory), an island of the Comoros archipelago, encountered its first CHIKV outbreak imported from Grand-Comore in mid-April 2005 (Renault et al. 2007), with 6346 reported cases (in two waves), observed by the surveillance system implemented throughout the island by the local French Health Authority, Dass (Direction des affaires sanitaires et socials) Mayotte. The first (minor) wave commenced in April 2005, it later peaked in week 18 and the infection rate diminished in June, with the virus maintaining low levels thereafter, during the temperate and dry season. However, the second (major) wave began during the first week of May 2006, peaked during the hottest and rainiest months around March/April 2006 and reduced to control levels by July 2006 (Sissoko et al. 2008).

In March 2005, a chikungunya infection which started in Grande-Comorre was imported into La Reunion (French Overseas Territory), becoming its first severe reported case involving two waves of outbreak, as observed by the epidemiological surveillance system implemented by the island's local Health Authorities (Renault et al. 2007). Firstly, a (minor) wave commenced in March 2005, peaked in May 2005 and decreased at the beginning of July to approximately 100 cases where the level was maintained during the austral winter. By December 2005 the second (major) wave began; however, the capacity of the surveillance system at the time was insufficient to evaluate the number of cases, as the number of cases was increasing exponentially. This resulted in an underestimation of the number of reported cases with possible misdiagnosis with Dengue fever which circulated the island the previous year (Renault et al. 2007). By April 2006, the Regional Health and Welfare Office reported 203 deaths that were directly (due to low immune status) or indirectly (in associations with other underlying conditions) attributed with chikungunya infection, with a low mortality rate of 0.3/1000 people (Renault et al. 2007).

The Maldives encountered its first CHIKV outbreak involving 11879 confirmed and suspected cases on 121 of the 197 inhabited islands, observed by the surveillance system implemented by the Epidemiology Unit of the Department of Public Health (DPH), from December 2006 to April 2007 (Yoosuf et al. 2008). The outbreak commenced at the beginning of December 2006, peaked in week 6 and subsided to control levels by week 11 before halting in April 2007. The epidemic was thought to be associated with post-tsunami construction activities which provided breeding sites for mosquitoes. Moreover, approximately five to six elderly patients died as result of co-morbidity and other conditions (Yoosuf et al. 2008).

Figure 2: Global Distribution of chikungunya virus, 1952 to 2009. The cases represented on the map are either confirmed cases or suspected cases (Evenor 2010).

References: 1 Krastinova et al. 2006, 2 Rezza et al. 2007, 3 Pastorino et al. 2004, 4 Sissoko et al. 2008, 5 Lumsden 1955, 6 Tamburro and Depertat 2009, 7 CDC 2009, 8 WHO 2008, 9 Yoosuf et al. 2009, 10 Leroy et al. 2009.

Importation into Europe

England

In 2006, the United Kingdoms' (UK) Health Protection Agency's (HPA) Special Pathogens Reference Unit (SPRU) reported 133 imported cases of chikungunya (Table 4). The majority of these tourists had travelled to the Indian Ocean islands (68), between March and August 2006, where outbreaks were circulating, with Mauritius being the main destination site involving 58 imported cases, followed by 6 in the Seychelles, and 4 in Madagascar. However, when the outbreaks were in decline, only one case was detected in December (HPA 2007). Between August and December, 44 cases were imported from India and 10 cases were imported from Sri Lanka, between November and December; countries with reported recent chikungunya outbreaks. Also imported into the UK, where one case from Nigeria, one from Tanzania, one case from Kenya, and one case from Australia. There had been no mention of chikungunya outbreak in these countries. However, the article did not state whether there had been reported sightings of Aedes mosquitoes in UK (HPA 2007).

Table 4. The number of cases was identified by different methods from the 133 imported cases, in the UK.

Identification of the imported cases

Number of cases

Laboratory confirmed case

45

Probable case

30

Suspected case

35

Past exposure

23

France

The Pitié-Salpêtrière Hospital in Paris, France, reported 80 cases of Chikungunya infection imported by tourists who recently visited the Southwest Indian Ocean region, between March 2005 and August 2006. The majority of cases (52) were imported from La Reunion (Hochedez et al. 2007), a popular destination site for French tourists (HPA 2006). Other destination sites reported were; Mauritius with 18, Comoros with 4, Madagascar with 3, and Mayotte with 2 cases (Hochedez et al. 2007). Within the same period, Metropolitan France reported 766 imported cases, which correlated with the two waves of the La Reunion outbreak (Figure 3). At the peak of the first La Reunion outbreak, an average of 20 cases was imported to France monthly. However, between August and November 2005, during the Southern Hemisphere winter, the cases decreased (Krastinova et al. 2006). A month after the peak of the second outbreak, the number of imported cases drastically increased. It can be argued that France is at risk of future outbreaks, in view that some of its inhabitants are constantly visiting the Southwest Indian Ocean regions (Hochedez et al. 2007), mainly La Reunion and also due to the inhabitation of Aedes albopictus (Krastinova et al. 2006).

Figure 3: Correlation between imported cases of Chikunugunya in metropolitan France to the estimated number of cases in the La Reunion outbreak (Krastinova et al. 2006).

Italy

Chikungunya was apparently imported into Italy by a male tourist coming from the Kerala province in India, who developed febrile illness two days into his holiday. The region he visited was Castiglonia di Cervia in June 2007. This was recorded by Ravenna province's local health unit in the Emilia Romagna region, northeastern Italy where 205 people developed CHIKV infection (Rezza et al. 2007). The vector, Aedes albopictus, was implicated in the spread of the virus which was then imported from Castiglione di Cervia into Castiglione de Revenna two villages separated by a river. Mosquito control measures implemented in the area resulted in a reduction in chikungunya infection. However, the control measure was not implemented in other villages and therefore a new wave occurred. The virus isolated from the outbreak contained the same mutational change (Ala226Val) in the membrane fusion E1 glycoprotein as the Indian Ocean variant, thereby suggesting that the Kerala strain could have originated from the Indian Ocean outbreak (Rezza et al. 2007).

Other European Countries

Tourism has been one of the main methods of CHIKV distributions worldwide, including its importation into several European countries. In 2006, the Bernhard-Nocht Institute for Tropical Medicine in Hamburg, Germany examined 720 samples from 680 European patients who became symptomatic upon return to Germany, Belgium, Switzerland, Denmark, and Poland from several destinations (Table 2) (Panning et al. 2008). The majority of patients had recently visited countries in the Indian Oceans; Mauritius, the Seychelles, La Reunion and Madagascar, and other countries; Bali, Indonesia, Sri Lanka, India, Malaysia, Kenya and Thailand. Moreover, most of these countries have been implicated in recent CHIKV outbreaks. No outbreaks were reported in these European countries; however, future outbreaks can be hypothesised (Panning et al. 2008).

Table 5. The country of origin and the holiday destinations of patients presented at the Bernhard-Nocht Institute for Tropical Medicine in Hamburg, Germany. Exact destinations were only available for 27.8% of patients, and exact itinerary were not available (Panning et al. 2008).

Country of origin

Number of patients

Germany

515

Belgium

99

Switzerland

42

Denmark

22

Poland

2

Total Nos. of patients

680

Holiday Destinations (Regions with Chikungunya Epidemic)

Number of patients

Mauritius

92

The Seychelles

23

La Reunion

18

Madagascar

9

Bali

2

Indonesia

6

Sri Lanka

5

India

28

Malaysia

2

Kenya

1

Thailand

3

Concurrence with Dengue Fever and Malaria

In 2006 and 2007, Madagascar and Gabon reported co-infections between Chikungunya and DENV-1 or DENV-2 respectively (Ratsitorahina et al. 2008, Leroy et al. 2009). Contrary to CHIKV, dengue virus (DENV) is of Flavirivirus genus from Flaviridae family; consisting of four antigenically distinct but closely related serotypes (DENV1-4). It is transmitted by Aedes aegypti and Aedes albopictus, also CHIKV transmission vectors (Cook and Zumla 2009). DENV and CHIKV have similar clinical features (Yoosuf et al. 2008). However, the only difference is that CHIKV has arthalgia (). The extended incubation period of DENV (5-8 days) differentiated it from CHIKV (2-7 days); however, the difference is insignificant (Cook and Zumla 2009). Thus, serological diagnosis can be used to differentiate DENV to CHIKV (Ratsitorahina et al. 2008). Ratsitorahina et al. (2008) and Leroy et al. (2009) confirmed Aedes albopictus as the predominating transmission vector of both CHIKV and DENV1 or 2. However, neither study stated whether the vector could simultaneously harbour both viruses. Moreover, the study by Vazeille et al. (2008) demonstrated that Aedes aegypti has a higher susceptibility to DENV-2 virus and a lower susceptibility to CHIKV; whereas Aedes albopictus is a more efficient vector for CHIKV than DENV-2 (Vazeille et al. 2008 and Moutailler et al. 2009). Leroy et al. (2009) further demonstrated this theory in the Gabon outbreak, as the majority of the patients had CHIKV compared to DENV-2.

In May 1999 and February 2000, the Matete and Kingabwa quarters of Kinshasa in the Democratic Republic of Congo (DRC) reported two Chikungunya outbreaks. CHIKV was the main contributing factor in the first outbreak; however, during the second outbreak, evidence confirmed possibility of co-infections between CHIKV and Plasmodium falciparum (Pastorino et al. 2004). Malaria is a parasitic infection, of the Apicomlexa phylum, that mainly infects host's red blood cells. It is transmitted by Anopheles species, whereas CHIKV is mainly transmitted by Aedes species. Plasmodium falciparum is one of the four species of Human Malaria (including Plasmodium vivax, Plasmodium malariae, and Plasmodium ovale). However, Plasmodium falciparum is the most severe form of Malaria (Cook and Zumla 2009). Pastorino et al. (2004) hypothesised that co-infections could be due to long term latency of Plasmodium falciparum, the presence of both transmission vectors in the area or the pathogens sharing the same vectors. An experimental investigation by Yadav et al. (2003 as cited by Pastorino et al. 2004) demonstrated that urban Anopheles stephensi (Plasmodium falciparum vector) could transmit CHIKV.

Lack of Research

We are still in the preliminary stages of understanding the interaction between CHIKV and host immunity (Kam et al. 2009), despite increasing number of reported outbreaks, there are insufficient evidences of up-to-date quality research (Panning et al. 2008). Therefore, outbreaks should be utilised to implement entomological and epidemiological system in improving our poor knowledge of the virus (Pialoux et al. 2007). Chretien and Linthicum (2007) argued that the Italian outbreak should provide opportunities for developed countries to strengthen the public-health system of developing countries in order to reduce the worldwide spread of outbreaks. These can be done by implementing Entomological and Virological surveillance in Aedes albopictus infested areas (Charell et al. 2008). Renault et al. (2007) utilised Deltamethrin insecticides to eradicate adult mosquitoes, whereas Rezza et al. (2007) utilised synergised pyrethrins. Furthermore, both authors utilised the biological larvicide, Bacillus thuringiensis israelensis, to destroy breeding sites (Renault et al. 2007, Rezza et al. 2007); however, Renault et al. (2007) later utilised Fenitrothion and temephos. Other control measures include educating the community on personal protection (Ratsitorahina et al. 2008). Although, no commercial vaccine has been approved, several candidates have been tested including the Formalin inactivated CHIKV vaccine for the Indian strain, DRDE-06, ECSA genotype (Tiwari et al. 2009). Therefore, the author believes that future outbreaks can be avoided if more research on CHIKV is undertaken, and a worldwide surveillance system is implemented.

Conclusion

This review has demonstrated that tourism is one of the main methods of CHIKV distributions worldwide, as it was the reason of several outbreaks. CHIKV was transported throughout the Southwestern Indian Ocean islands by viraemic tourists visiting different islands (Figure 2) and Kerala, India, which was then imported into Italy (Renault et al. 2007, Rezza et al. 2007, Sissoko et al. 2008, Yoosuf et al. 2008). However, outbreaks require temperatures above 20oC and annual rainfall over 500mm to maintain Aedes mosquitoes' populations (Straetemans 2008, Tilson et al. 2009). Therefore, England is one of the least at risk country, as Aedes albopictus is not present, and the temperature is unfavourable to maintain mosquitoes' life cycle (HPA 2007, Met Office 2010). Countries such as France and Italy are at high risk, due to the presence of Aedes albopictus and the introduction of CHIKV; although, Italy is the most at risk due to a recent outbreak (Krastinova et al. 2006, Rezza et al. 2007). The eminent climatic changes could result in rising temperatures and increased rainfall that would favour the establishment of Aedes albopictus worldwide. All these emphasises the need for Western medicine to plan for future CHIKV outbreaks, by implementing a worldwide surveillance system in order to monitor outbreaks and to perform vector control measures (Charell et al. 2008). Chikungunya have concurrence with Malaria and Dengue Fever (Leroy et al. 2009, Ratsitorahina et al. 2008); furthermore, evidence suggests wrong classification of Chikungunya due to its resemblance to Dengue fever. CHIKV is constantly mutating, thus constant development of a new vaccine is required (Tiwari et al. 2009). Thereby, further researches are needed.

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