A review of the experience of childhood hepatitis A vaccination in Saudi Arabia and Turkey: implications for hepatitis A control and prevention in the Middle East and North African region

ABSTRACT

In most countries of the Middle East and Northern African (MENA) region, a high hepatitis A virus (HAV) endemicity has been documented. Few others, such as Saudi Arabia and Turkey, are transitioning from high to intermediate endemicity. There is a paucity of recently published HAV disease burden that could be useful to inform or strengthen relevant national hepatitis A vaccination policy and other prevention strategies in the region. This review summarizes information on HAV epidemiology before and after the implementation of a childhood hepatitis A vaccination program in Saudi Arabia and Turkey. In both countries, a clear shift in the age of first HAV exposure has been documented, with more homogeneous trends across regions in Saudi Arabia compared to Turkey. Utilizing the experience of Saudi Arabia and Turkey with hepatitis A vaccination, countries in the region are encouraged to foster discussions on potential vaccination strategies suitable for their own setting.

KEYWORDS:

• Hepatitis A
• endemicity
• Middle East
• Saudi Arabia
• seroprevalence
• Turkey
• vaccination

Introduction

The hepatitis A virus (HAV) is a common infectious etiological agent of acute viral hepatitis.¹ It is frequently transmitted through the fecal-oral route and is acquired by mouth when a HAV-naive person ingests contaminated food or water or comes into close contact with an infectious person.^1,2 It is challenging to diagnose hepatitis A from other types of viral hepatitis solely on the basis of clinical attributes. Therefore, serologic testing to confirm the presence of antibodies is required for diagnosis. While anti-HAV IgM antibodies indicate recent or current infection, IgG antibodies indicate past infection and usually persist throughout an individual’s lifespan after infection or vaccination.¹ HAV infection is confirmed in the acute or early convalescent phase of infection by the presence of anti-HAV immunoglobulin M (IgM) in serum, typically at detectable levels 5–10 days before the onset of symptoms and up to 6 months after infection with HAV. Anti-HAV immunoglobulin G (IgG) is also detected in the serum during the convalescent phase of infection, and remains in the serum throughout the lifetime of an individual, providing protection against disease during a future infection.¹ Together, these measures prove useful in providing important epidemiological insights and HAV seroprevalence estimates.³

Infection with HAV is very common in the early years of life and is often asymptomatic among children below 6 years of age (YOA).¹ In older individuals, the disease is associated with an abrupt onset of symptoms: low-grade fever, malaise, anorexia, nausea, loss of appetite, abdominal discomfort or jaundice.¹ The majority of the clinical illnesses due to HAV tends to resolve itself within 2 months after infection, with approximately 10%–15% of individuals developing prolonged or relapsing symptoms lasting up to half a year.¹ When relapse occurs, hepatitis may cause severe complications such as fulminant hepatitis or acute liver failure and, in some cases, even death.¹ Importantly, the severity and clinical outcome ensuing HAV infection is determined mostly by the age of the infected individual, that is, HAV infection is associated with more severe disease, a higher risk of fulminant hepatitis and death with progressing age of the individual.¹

Worldwide, hepatitis A disease occurs sporadically, with a trend of cyclic recurrences.² HAV is estimated to be responsible for approximately 1.5 million clinical cases of viral hepatitis per year.⁴ In high-income countries, hepatitis A accounts for 20–25% of the total viral hepatitis burden whereas this burden is expected to be higher in low- and middle-income countries.^5,6 This is primarily due to improving socioeconomic indicators such as rising incomes and access to clean water and sanitation,^7–9 which has led to the evolution of HAV epidemiology over the last two decades. Four levels of HAV endemicity are defined according to the World Health Organization (WHO) on the basis of seroprevalence (anti-HAV IgG): high (≥90% by 10 YOA); intermediate (≥50% by 15 YOA, with <90% by 10 YOA); low (≥50% by 30 YOA, with <50% by 15 YOA); and very low (<50% by 30 YOA).¹⁰ Paradoxically, a gradual transition from high to intermediate endemicity has been documented in several low- and middle-income countries, significantly increasing the incidence of clinical hepatitis A.^8,9,11,12 Additionally, this shift in endemicity could lead to outbreaks in susceptible populations who have not been exposed to HAV in their life and do not have immunity.^2,10 Consequently, this can be a source of burden on individuals due to impact on quality of life, and direct and indirect financial burden on families and health-care systems resulting from absence from work or school for several weeks or months.¹³

Immunization against HAV is considered an effective intervention to prevent clinical hepatitis A. Both the inactivated and live attenuated hepatitis A vaccines are highly immunogenic, well-tolerated and safe in the target vaccine populace and generate long-lasting, possibly life-long, protection against hepatitis A.^14–16 The WHO recommends that vaccinations against HAV be integrated into the national immunization schedule for children ≥1 YOA if indicated on the basis of incidence of acute hepatitis A, change in the endemicity from high to intermediate, and consideration of cost-effectiveness.¹⁰ Noting this recommendation, the WHO states that vaccination against hepatitis A should be part of a comprehensive plan for the prevention and control of viral hepatitis, including measures to improve hygiene and sanitation and measures for outbreak control. Countries that have seen rapid improvements in socioeconomic status may move from high to intermediate hepatitis A endemicity in a short span of time. In these countries, a relatively large proportion of the adult population would be susceptible to HAV and therefore large-scale hepatitis A vaccination is likely to be cost-effective.¹⁰ To implement decision-making of an appropriate vaccination program in an individual country, robust epidemiological data is needed. In terms of assessing any shifts in HAV endemicity, age-specific HAV seroprevalence rates and age at the midpoint of population immunity (AMPI) are reliable indicators to ascertain the hepatitis A situation in a country.¹⁷ Establishing HAV seroprevalence (measurement of anti-HAV IgG or combined anti-HAV IgG/IgM antibodies) by age facilitates the indirect measurement of age-specific incidence rates of infection by providing a measurement of the susceptibility of the age group to new infections. This is useful to understand the concept of transition and shifting of the risk to individuals of older ages that have not been infected in childhood.³

Hepatitis A in the Middle East and North Africa (MENA) region

In the Middle East and Northern African (MENA) region, several countries, such as Iran, Jordan, Lebanon, Morocco, Tunisia, Egypt, Iraq, Palestine, Syria, and Yemen have high or very high levels of HAV endemicity.^18,19 Among other countries in the region, such as Algeria, Saudi Arabia, Turkey, Kuwait, and the United Arab Emirates, substantial progress in the socioeconomic levels, sanitary conditions, access to clean water sources, and improvements in the quality of water has been documented, resulting in a transition in HAV endemicity levels.^20–22 A few of these countries have also implemented childhood hepatitis A vaccination programs.^23,24 Given these developments in recent decades, a gradual shift in the age at infection with HAV has been observed in a few of these countries in the MENA region.^20–22 This phenomenon deserves urgent attention as it may lead to the occurrence of regular community-wide outbreaks, the consequences of which can be grave in the populations without immunity (such as adolescents and adults) in the region.^20–22

Published literature on HAV disease epidemiology and burden from the MENA region is often either outdated or missing. Adding to these issues is the limited experience of childhood hepatitis A vaccination programs from countries in the MENA region. These data are essential to help countries design appropriate interventional strategies to circumvent HAV disease burden. Moreover, if experience from vaccination programs from the region is available, it can be leveraged upon by other countries in the region without such programs to establish or strengthen relevant national hepatitis A vaccination policy.

Review objectives and methods

This review aims to summarize publicly available information to offer insights into the evolving pattern of HAV epidemiology in the MENA region before and after the implementation of a childhood vaccination program. Here, we used the examples of Saudi Arabia and Turkey, two countries which were among the first countries to introduce such a program into their national immunization calendars.

To collect information relevant to Saudi Arabia and Turkey, we identified published literature in PubMed (via Medline; search cutoff date: July 10, 2020) using the following search strategy: “hepatitis A” AND “Country” AND (“seroprevalence” OR “incidence”). Published estimates from the original research were supplemented with data from the Ministry of Health websites of Saudi Arabia (data available from the year 2005)²³ and Turkey (data available from the year 2007).²⁴ A gray literature source was consulted to obtain insights into the countries profiles.^25,26 Articles published in English language and local languages were considered in this review. Outcomes of interest included estimates of epidemiology, such as new cases, incidence rate (per 100,000) and deaths due to HAV. When available, disease time trends and disease trends by age group, seasonality, region, gender, nationality, and other socioeconomic indicators (living standards [urban, rural], income level, migration patterns, etc.) have been extracted from the source publications and presented.

Hepatitis A in Saudi Arabia

Country profile

Saudi Arabia, officially known as the Kingdom of Saudi Arabia, is the second largest Arab, located in and making most of the Arabian Peninsula. The population of Saudi Arabia is estimated to be around 35 million (2020), and is reported to have between 3 and 5 million illegal immigrants from neighboring countries residing within its borders. Given its large area of 2.15 million square kilometers, the population density is approximately 16 individuals per square kilometer.²⁵

Individuals of 15–64 YOA constitute the majority of the total population (64.8%), whereas individuals of 0–14 YOA form nearly one-third (32.4%) and older adults (≥65 YOA) constitute 2.8% of the total population of Saudi Arabia. The median age in Saudi Arabia is 27.5 YOA with a life expectancy of 75.5 YOA (2020). This is likely influenced by improvements in provision of safe and clean drinking water, high performance of sanitation facility, and 4.7% of their Gross Domestic Product (GDP) expenditure on healthcare. A large proportion (83.3%) of Saudi Arabia’s population lives in urban areas, meaning that there are several large cities in the country. The capital, Riyadh, is the largest with a population of around 6.5 million, followed by Jeddah with roughly 4 million inhabitants and others, such as Mecca, Medina, Hofuf, and Ta’if that all have large populations ranging between 1 and 2 million.²⁵ Mecca and Medina also host the Hajj which leads to millions of pilgrims congregating from over 180 countries around the world every year.

Evolution of HAV epidemiology

The epidemiology of hepatitis A in Saudi Arabia has undergone major changes, concurrent with major socioeconomic developments over the last two to three decades. We found little published evidence on the incidence of hepatitis A but several studies did provide data on HAV seroprevalence in Saudi Arabia (Table 1).^27–29

Table 1. HAV seroprevalence in Saudi Arabia

					HAV Seroprevalence (%)
Reference	Study period	National/Regional	Age group of study population	Study setting	Overall	By age	By region	By gender	By nationality	Other variables
Pre-vaccine introduction
Alshabanat et al.^Citation27	January 2006 – December 2010	National	Not specified	Retrospective cross-sectional analysis	17% (among hepatitis cases)	5–14 YOA: 60.2% of all viral hepatitis cases	Najran (n = 837, 11.1%) Riyadh (n = 817, 10.8%) Qaseem (n = 779, 10.3%) Jazan (n = 706, 9.3%)	n.r	n.r	n.r
Babaeer et al.^Citation30	n/a	Jeddah	<2 YOA	Laboratory-based	33.1%	2–5 YOA: 17% 6–9 YOA: 21.9% 10–14 YOA: 28.8% 15–19 YOA: 27.2% 20–24 YOA: 34.3% 25–29 YOA: 38.2% 30–34 YOA: 47.7% ≥ 35 YOA: 49.2% Adults versus children: 39.3% versus 22.4% (p < .05)	n.r	Male: 33.6% Female: 32.5% (not significant)	Saudi: 20.3% Non-Saudi: 49% (p < .05)	n.r
Al Faleh et al.^Citation35	December 2007 – January 2008	Medina, Al-Qaseem, and Aseer	16–18 YOA	Community-based	2007–2008: 18.6% 1997: 24.3% 1989: 53.1%	n.r	2007–2008: Medina: 27.4% (p < .0001) Aseer: 13.5% Al-Qaseem: 13.9% 1997: Medina: 26.2% (p < .0001) Aseer: 18.9% Al-Qaseem: 31.5% 1989: Medina: 59.4% (p < .0001) Aseer: 44.5% Al-Qaseem: 61.1%	Male: 21% Female: 16.2%	n.r	High socioeconomic level: 5.9% Upper middle socioeconomic level: 9.6%: Lower middle socioeconomic level: 16.6% Low socioeconomic level: 36.8%
Hendrickx et al.^Citation28	30 November – 1 December 2007	National	n/a	Meeting report	n.r	Before 1990: Children 1–18 YOA: 50–92% During 1990s: Children 1–15 YOA (higher prevalence in older children): 25–30% In 2005: <8 YOA: 7.1% 8–11 YOA: 14.5% 12–15 YOA: 30.6% >16 YOA: 52.0%	n.r	n.r	n.r	n.r
Memish et al.^Citation29	January 2000 – December 2007	Central, Eastern, and Western Saudi Arabia regions	<15 YOA-≥15 YOA	Laboratory-based surveillance study	n.r	<15 YOA: 81.9% ≥15 YOA: 18.1%	Central region: 59.5% (p < .001) Western region: 22.6% Eastern region: 17.8%	Male: 55.2% (p < .001) Female: 44.8%	Saudi: 98.4% Non-Saudi: 1.6% (p < .001)	n.r
El-Gilany et al.^Citation34	February 2006 – January 2007	Northern borders region	1–6 YOA	Cross-sectional sero-epidemiological study	33.8%	1 -<3 YOA: 18.9% 3 -<5 YOA: 33.6%; p < .001 5 -<7 YOA: 44.1%; p < .001	n.r	Male: 35.5% Female: 32.0% (p = .247)	Saudi: 32.7% Non-Saudi: 43.1% (p = .035)	Urban: 27.5% Rural: 57.5% (p < .001)
Almuneef et al.^Citation36	March 2005	Riyadh area	4–18 YOA	Community-based	28.9%	<8 YOA: 7.08% 8–11 YOA: 14.46% 12–15 YOA: 30.55% >16 YOA: 52.03%	n.r	Male: 28.2% Female: 29.5%	n.r	n.r
Jaber^Citation37	2004	Jeddah	4–14 YOA; 49% received HAV vaccination	School setting; laboratory-based	28.7%	Vaccinated 4–6 YOA: 14.8% 7–11 YOA: 38.3% 12–14 YOA: 28.6% Non-vaccinated 4–6 YOA: 14.7% 7–11 YOA: 38.1% 12–14 YOA: 28.0%	n.r	Vaccinated Male: 10.0% Female: 19.0%, p < .05 Non-vaccinated Male: 19.0% Female: 10.0%, p < .01	Vaccinated Saudi: 14.0% Non-Saudi: 15.0%, p > .05 Non-vaccinated Saudi: 19.0% Non-Saudi: 10.0%, p < .01	Vaccinated: 29.0% Non-vaccinated: 29.0%, p > .05
Almuneef et al.^Citation38	September 2001 – March 2005	Riyadh	HCWs >20 YOA	Hospital-based, prospective cohort study	67.0%	20–29 YOA: 56.0% 30–39 YOA: 81.0% 40–49 YOA: 87.0% ≥50 YOA: 86.0%	n.r	Male: 76.0%; Female: 60.0% p < .001	Middle East: 63.0% Far East: 77.0% West: 82.0% Africa: 71.0%	n.r
Al Tawfiq et al.^Citation39	January 2000-June 2005	Eastern Province of Saudi Arabia	all	Hospital-based	10%	<2 YOA: 5.8% 3–6 YOA: 15.8% 7–12 YOA: 42.5% 13–20 YOA: 26.7% <20 YOA: 9.2%	n.r	n.r	n.r	n.r
Memish et al.^Citation40	1999–2001	Riyadh	all	Hospital-based	1999: 6.7% 2000: 6.9% 2001: 10.7%	IgM: 1999 – 1–10 YOA: 55.0% 11–20 YOA: 41.3% 21–30 YOA: 3.8% >30 YOA: 0.0% 2000 – 1–10 YOA: 63.9% 11–20 YOA: 30.6% 21–30 YOA: 5.6% >30 YOA: 0.0% 2001 – 1–10 YOA: 71.6% 11–20 YOA: 26.9% 21–30 YOA: 1.5% >30 YOA: 0.0%	n.r	Male/Female ratio 1:1	n.r	n.r
Fathalla et al.^Citation32	February 1987 – January 1999	Eastern Saudi Arabia	all	Laboratory-based	86.0%	<6 YOA: 3% 6 – <8 YOA: 62% 8 – <10 YOA: 71% 10 – <12 YOA: 83% 12 – <18 YOA: 93% Overall among children: 79%	n.r	n.r	n.r	n.r
Al Faleh et al.^Citation33	1997	National	1–12 YOA	Randomized community-based study	1997: 25.0% 1989: 51.0% (p < .0001)	1997: 1–2 YOA: 16.0% 3–4 YOA: 22.0% 5–6 YOA: 25.0% 7–8 YOA: 29.0% 9–10 YOA: 34.0% 11–12 YOA: 34.0% 1989: 1–2 YOA: 31.0% 3–4 YOA: 43.0% 5–6 YOA: 51.0% 7–8 YOA: 60.0% 9–10 YOA: 68.0% 11–12 YOA: n.r	n.r	n.r	n.r	Urban: 21.0% Rural: 33.0%
Barrimah et al.^Citation41	January-May 1996	Jeddah	All ages	Outbreak investigation and case control study	IgM: 94 cases	n.r	n.r	n.r	n.r	n.r
Khalil et al.^Citation43	April 1995 – February 1996	Riyadh area	<16 YOA	Community-based	30.2%	0.5–2 YOA: 12.5% 3–4 YOA: 14.7% 5–6 YOA: 20.3% 7–8 YOA: 40.4% 9–10 YOA: 32.0% 11–12 YOA: 44.3% 13–15 YOA: 48.6%	n.r	n.r	Saudi: 28% Middle Eastern: 41.0% Other: 3.0% (p = .022)	High social level: 25.9% Medium social level: 28.9% Low social level: 40.9% (p = .044) Rural: 38.9% Urban: 28.4% Bedouin: 26.3% (p = .094)
Arif et al.^Citation44	July 1993 – May 1994	Riyadh area	1–30 YOA	Hospital-based	60.2% (overall prevalence)	1 to 12 YOA: 88.2% 15 to 24 YOA: 11.8%	n.r	n.r	Saudi 1–30 YOA: 1994: 50.2% 1986: 76.5%; p < .005	n.r
Al-Knawy et al.^Citation45	n/a	Southern Saudi Arabia	>3 YOA	Hospital-based	81.8%	n.r	n.r	n.r	n.r	n.r
Ghabrah et al.^Citation46	1992	Jeddah, Mecca	Patients with acute viral hepatitis ≥13 YOA	Hospital-based	Evidence of prior exposure in 206/217 cases	n.r	n.r	n.r	Almost all 11 HAV cases were from Saudi Arabia or the Middle East	n.r
Al Rashed et al.^Citation42	December 1989 – January 1990	National	1–10 YOA	Community-based	52.4%	Children <3 YOA: 36% Children <7 YOA: 63.8%	Central region: 52.6% Eastern region: 38.4% Northwestern region: 67.0% Southwestern region: 41.6% Southern region: 62.1%	Male: 51.3% Female: 53.5%	n.r	High social level: 35.0% Medium social level: 48.5% Low social level: 59.0%
Ramia et al.^Citation47	n.r	Riyadh area	all	Laboratory-based	82.5%	<1 YOA: 67.9% (high due to passively acquired maternal antibodies) 1–4 YOA: 38.6% 5–9 YOA: 61.3% 10–15 YOA: 81.5% 16–19 YOA: 83.5% 20–29 YOA: 91.0% 30–39 YOA: 93.5% ≥40 YOA: 95.0%	n.r	n.r	n.r	n.r
Ashraf et al.^Citation31	August 1984 – July 1985	Gizan area	all	Hospital-based	n.r	<0.5 YOA: 66.0% 0.5–2 YOA: 60.0% 3–5 YOA: 83.0% 6–12 YOA: 98.0% >12 YOA: 100%	n.r	n.r	Saudi: 89% Expatriates: 26%-92% (depending on nationality)	n.r
Talukder et al.^Citation48	n/a	Riyadh area	n.r	Hospital-based	92.9%	n.r	n.r	n.r	n.r	n.r

HAV, hepatitis A virus; HCW, health care worker; IgM, immunoglobulin M; n/a, not available; n.r, not reported; YOA, years of age.

^¥Unless otherwise specified, HAV seroprevalence results indicate measurements of IgG.

The incidence of hepatitis A cases was found in three studies.^27–29 One study reported a decline in incidence from 14.0 per 100,000 to 9.0 per 100,000 from 1992 to 2003.²⁸ After an outbreak in 2004, incidence resumed its decline with 8.0 per 100,000 in 2007, with the highest incidence reported in the Eastern region of Saudi Arabia compared to Central and Western regions; in males compared to females; in Saudi nationals compared to non-Saudi nationals; and in children <15 YOA compared to individuals ≥15 YOA.²⁹ A third study reported an incidence of 8.02 per 100,000 in 2008 (based on data from the Ministry of Health).²⁷

Evidence from studies investigating HAV seroprevalence reveal an overall decline in HAV seroprevalence regardless of age in the 1990s compared to those rates reported from studies conducted in the 1980s. Specifically, seroprevalence surveys in the 1980s usually found a prevalence of nearly 90% by 10 YOA but in the 1990s, more than 50% of children under 10 YOA; and more than 90% of teenagers had immunity to HAV, a serological heritage of past exposure.^31,32 Into the early years of the twenty-first century, about one-third of the adolescent population and >50% of young adults (≥20 YOA) had immunity to HAV. The majority of studies provides evidence of differences in seroprevalence by age group (higher HAV seropositivity in older individuals compared to children), and regions/cities (higher HAV seropositivity in individuals from underdeveloped Central and Western regions of Saudi Arabia than individuals from other regions). Limited data was found to support differences in HAV seroprevalence by gender and nationality of the individual (Table 1). A few studies did report stark differences in HAV seroprevalence by urban or rural living conditions within regions or cities^33,34 and socioeconomic stratifications, most likely affected by the community’s socioeconomic development, in terms of education, housing conditions, water sanitation, GDP and improvements in healthcare infrastructure.

In terms of healthcare infrastructure, Saudi Arabia implemented childhood hepatitis A vaccination in its universal mass vaccination program in 2008. Since its implementation, hepatitis A vaccination is given as a two-dose schedule to children at 18 and 24 months of age. Three hepatitis A vaccines are licensed in Saudi Arabia, of which two vaccines are available through its universal mass vaccination program: Avaxim (Sanofi Pasteur) and Healive (Sinovac Biotech Ltd); both of which are inactivated hepatitis A vaccines. Publications describing the epidemiology and disease burden of HAV after the implementation of vaccination are available from the Ministry of Health of Saudi Arabia.²⁷ One publication that performed a cross-sectional analysis on data from the Ministry of Health show a much more pronounced decline in HAV incidence (from 8.02 per 100,000 in 2008 to 2.54 per 100,000 in 2010) after the implementation of the childhood hepatitis A immunization program.²⁷ Time trends of the number of total cases and incidence of HAV have also been made available by the Ministry of Health of Saudi Arabia (Figure 1(a-e)). The data shows that since 2008, the total number of new hepatitis A cases has declined by about 90% (Figure 1(a)). A corresponding decline in the incidence rate was observed, albeit with a small increase from 0.42 per 100,000 to 0.74 per 100,000 from 2016 to 2018 (Figure 1(b)). Yet a significant increase (147%) in the total number of hepatitis A cases was documented from 2016 to 2018, with adults of 15–44 YOA and >45 YOA being the most impacted age group (Figure 1(c)). Together, these data demonstrate a more distinct and sustained shift in HAV endemicity (i.e. the age at first infection with HAV) than that observed prior to the implementation of childhood vaccination in Saudi Arabia. In terms of trends in disease occurrence, a low number of hepatitis A cases has been reported in the summer season with a gradual shift in seasonality since 2014, with most hepatitis A cases being reported in the autumn seasons in the latter years (Figure 1(d)). While the overall number of hepatitis A cases and incidence rate have declined in Saudi Arabia, there is significant heterogeneity reported across the different regions and cities of Saudi Arabia, with the highest incidence rate reported in Qurayyat followed by Najran (Figure 1(e)). Qurayyat and Najran share their borders with Jordan and Yemen, respectively. While the hepatitis A burden in Jordan is comparable to this of Saudi Arabia, Yemen is suggested to have a high burden of hepatitis A.¹⁹ Moreover, the vast majority of the populations in both cities are Bedouins who tend to live in rural areas and have to cope with inadequate water and sanitation facilities.

Figure 1. Evolution of hepatitis A in Saudi Arabia (a) Total number of cases (b) Incidence rate (c) Age-specific distribution of cases (d) Seasonal distribution of cases (e) Regional distribution of cases

Source: Ministry of Health, Saudi Arabia (2005–2018)²³*Implementation of childhood hepatitis A vaccination in the Saudi Arabian UMV. UMV, universal mass vaccination; UNK, unknown; YOA, years of age.

Hepatitis A in Turkey

Country profile

Turkey, officially known as the Republic of Turkey, is a trans-continental country that includes Anatolia in West Asia and East Thrace in Southern Europe. The population of Turkey is estimated to be around 84 million (2020) with about 3,600,000 immigrants. Given its area of 769,630 square kilometers, the population density is approximately 110 individuals per square kilometer.²⁶

Individuals of 15–64 YOA constitute a majority of the total population (67.0%), whereas individuals of 0–14 YOA represent 27.0% of the total population. Older adults (≥65 YOA) account for 6.0% of the total population. The median age in Turkey is 30.9 years with a life expectancy of 75 YOA (2018).²⁶ This is likely influenced by socioeconomic and health-care improvements seen in recent decades. Notably, the entire population of Turkey has access to safe and clean drinking water and only 5% of the population struggles with access to improved sanitation facilities. A large proportion (70%) of Turkey’s population live in urban areas and the country harbors several large cities. The largest city, Istanbul, has a population of nearly 15 million, followed by the capital, Ankara, with 3.5 million inhabitants, and others such as Izmir, Bursa, Adana and Gaziantep that have large populations comprised between 1 and 2 million.²⁶

Evolution of HAV epidemiology

In the early 1990s, HAV disease was highly endemic in Turkey. Owing to gradual improvements in hygiene and sanitary conditions in Turkey, the burden of disease due to HAV saw a steady decline. We found one study that provided the incidence of hepatitis A cases; in 2004, 6.6 to 19.7 per 100,000 depending on the region with the highest incidence reported in 5- to 14 YOA followed by individuals >15 YOA.²⁸

Several studies have investigated HAV seroprevalence in Turkey (Table 2). While studies from the 1990s show high HAV seroprevalence among more than half of all young adolescents,^35,42 studies performed in the 2000s show over half of the adolescent and young adult population with higher rates of HAV seropositivity, much higher than in children (Table 2). It is worth noting that the majority of data are reflective of a past infection with HAV (anti-HAV IgG) rather than a recent exposure (anti-HAV IgM); anti-HAV IgM levels when reported ranged from 0.0% to 22.7%, with children and adolescents ≤15 YOA being the most affected group, which can be explained by HAV infection occurring in schools.^43,49 This evidence is reflective of a change in HAV endemicity in Turkey with a marked decrease in the HAV seroprevalence in the overall population, and an apparent shift in the pattern of HAV exposure toward older children, adolescents and young adults.

Table 2. HAV seroprevalence in Turkey

					HAV Seroprevalence (%)
Reference	Study period	National/Regional	Age group of study population	Study setting	Overall	By age	By region	By gender	Other variables
Post-vaccine introduction
Yüksek et al.^Citation50	January 2008 – December 2015	Ankara	0–18 YOA	Hospital-based (inpatient)	Pre-vaccination: 68.2% Post-vaccination: 31.7%	n.r	n.r	n.r	n.r
Pre-vaccine introduction
Kader et al.^Citation51	January – June 2017	Yozgat	≥6 YOA without vaccination history	Cross-sectional survey	79.1%; p < .01	6–19 YOA: 52.2% 20–96 YOA: 93.9%; p < .001	n.r	n.r	n.r
Karadeniz et al.^Citation52	September 2016 – September 2017	Istanbul	18–61 YOA	Laboratory-based	33.9%	18–26 YOA: 29.4% 27–38 YOA: 92.9% >38 YOA: 89.3%	n.r	Female: 32.0% Male: 39.3%; p = .021	n.r
Köse et al.^Citation53	April 2014 – December 2015	Izmir	Syrian refugee children 0–18 YOA	Hospital-based	47.7%	n.r	n.r	n.r	n.r
Yentür Doni et al.^Citation54	January – April 2013	Southeastern Anatolia Region	Female farm workers 15–49 YOA	Cross-sectional survey	99.1%	15–19 YOA: 90.9% 20–49 YOA: 99.3%	n.r	n.r	Household size ≤6 members in household: 99.6% ≥7 members in household: 98.9% Number of pregnancies ≤4 pregnancies: 99.0% ≥5 pregnancies: 99.3% Education level Illiterate: 99.1% Primary school and above: 99.6% Poverty Yes: 99.2% No: 98.5% Access to water Unsafe: 99.2% Safe: 99.0% Toilet location Indoors: 99.0% Outdoors: 99.3%
Özden^Citation63	January 2011 – December 2014	Konya	Patients with chronic viral hepatitis of all ages	Hospital-based	94.2%	<20 YOA: 23.8% 21–30 YOA: 82.0% 31–40 YOA: 90.5% 41–50 YOA: 100% 51–60 YOA: 99.1% 61–70 YOA: 100% >70 YOA: 100%	n.r	Female: 94.3% Male: 94.2%; p > .05	Cirrhotic patients: 97.4% Non-cirrhotic patients: 93.9%; p > .05 City: 91.5% Town: 95.6% Rural area: 100%
Tulek et al.^Citation64	2009–2013	Ankara	Patients with chronic hepatitis B of 17–78 YOA	Hospital-based	90.5%	<20 YOA: 34.0% 20–29 YOA: 79.0% >35 YOA: 100%	n.r	n.r	n.r
Pirinccioglu et al.^Citation65	September – October 2011	Diyarbakır	7–14 YOA	Prospective investigation	45.7%	7 YOA: 13.3% 8 YOA: 23.7% 9 YOA: 37.0% 10 YOA: 46.0% 11 YOA: 46.8% 12 YOA: 60.3% 13 YOA: 66.7% 14 YOA: 73.7%	n.r	Male: 41.2% Female: 49.8% (p = .042)	n.r
Karacaer et al.^Citation66	n.r	All regions	17–89 YOA	Retrospective hospital-based	37.6%	<20 YOA, 30/821 21–30 YOA: 191/821 31–40 YOA: 82/821 41–50 YOA: 9/821 51–60 YOA: 3/821 61–70 YOA: 0/821  >71 YOA: 5/821	n.r	Male: 185/821 Female: 135/821	n.r
Dogru et al.^Citation59	2001–2011	All regions	0–14 YOA	Geographic Information Systems-based survey	n.r	5–9 YOA was strongly affected by HAV 0–4 YOA had the lowest infections	n.r	n.r	n.r
Nalbatoglu et al.^Citation57	March – November 2010	Tekirdağ, Thrace	6 months −12 YOA	Hospital-based (outpatient)	Anti-HAV IgM: 3.3%; Anti-HAV IgG: 25.4%	HAV IgM positive 6 months-1 YOA: 0.0% 2–6 YOA: 2.3% 7–12 YOA: 4.2%; p < .001 HAV IgG positive: 6 months-1 YOA: 12.5% 2–6 YOA: 16.1% 7–12 YOA: 34.0%; p < .001	n.r	n.r	Low-monthly-income families: 36.1% Intermediate-income families: 17% High-income families: 11.1%; p < .001 Anti-HAV IgG seropositivity in patients with no vaccination: 16.1% Maternal education >6 years: 16.2% ≤5 years: 45.3%
Ceran et al.^Citation67		Istanbul	5–24 YOA	Prospective laboratory-based	40.0%	5–9 YOA: 11.4% 10–14 YOA: 29.0% 15–19 YOA: 49.7% 20–24 YOA: 69.0%; p = .0001	n.r	Male: 38.2% Female: 41.3%; p = .440	Low socioeconomic level: 45.8% Middle or high socioeconomic level: 34.4%; p = .014 Maternal education level University: 12.0% High school: 19.6% Primary: 38.4% Literate: 52.0% Illiterate: 63.0%, p < .0001
Karaman et al.^Citation68	October – December 2009	Van (Eastern Turkey)	1–15 YOA	Hospital-based	54.9%	1–4 YOA: 26.2% 5–8 YOA: 52.3% 9–12 YOA: 72.6% 13–15 YOA: 80.6%	n.r	Male: 59.0%; Female: 41.0%; p = .342	<6 people in household: 41.7% ≥6 people in household: 63.3% Middle or high socioeconomic level: 45.0% Low socioeconomic level: 63.7%
Alhan et al.^Citation69	2009 compared to 1998	Adana	2–16 YOA	Laboratory-based	1998: 44.4%; 2009: n.r	2009: 2–4 YOA: 10.0% 4–6 YOA: 22.2% 6–8 YOA: 25.3% 8–10 YOA: 30.8% 10–12 YOA: 35.2% 12–14 YOA: 37.7% 14–16YOA: 47.3% 1998: 2–4 YOA: 10.6%; p > .05 4–6 YOA: 33.9%; p > .05 6–8 YOA: 29.5%; p > .05 8–10 YOA: 52.2%; p < .0001 10–12 YOA: 69.7%; p < .0001 12–14 YOA: 66.9%; p < .0001 14–16 YOA: 71.4%; p < .0001	n.r	n.r	n.r
Halicioglu et al.^Citation70	April – December 2009	Izmir	1–18 YOA	Cross-sectional study	29.5%	1–2 YOA: 21.4% 2.1–5 YOA: 15.1% 5.1–8 YOA: 20.1% 8.1–11 YOA: 32.6% 11.1–14 YOA: 44.3% 14.1–18 YOA: 52.4% ≤10 YOA versus >10 YOA: 21.6% versus 44.3%; p < .001	n.r	Male: 29.3% Female: 30.3%; p = .763	Family size (p < .001) ≤4 persons: 20.6% >4 persons: 40.4% Food service (p < .001) With separate dining plates: 19.1% Common dining plate: 54.2% Family income (p = .001) Low income: 31.0% Moderate income: 11.2% Parental education (p = .02) ≥6 years:18.8% ≤5 years: 31.0% Maternal education (p = .003) ≥6 years:14.8% ≤5 years: 31.0%
Viral Hepatitis Prevention Board,^Citation58	2008–2009	All regions	All ages	Population-based study	National level intermediate HAV endemicity	<30 YOA: 71.3% 1 YOA: 42.7%; 25–29 YOA: 91.1%	Western region >50%	n.r	n.r
Kurugöl et al.^Citation71	February – July 2008	Izmir	1–60 YOA	Laboratory-based	46.4%	2008: 1–4 YOA: 4.6% 5–6 YOA: 10.3% 7–9 YOA: 22.1% 10–14 YOA: 23.2% 15–19 YOA: 36.4% 20–29 YOA: 85.3% 30–39 YOA: 95.6% ≥ 40 YOA: 99.0% 1998: 1–4 YOA: 36.0% 10–14 YOA: 65.0% 20–29 YOA: 95.0%	n.r	Male: 34.7%; Female: 54.0%; p < .01	≥5 people in household: 59.5% <5 people in household: 39.2%; p < .01 Rural: 52.4% Urban: 45.1%; p = .175 Low socioeconomic level: 57.7% Medium or high socioeconomic level: 31.5%
Ince et al.^Citation72	August 2007 – February 2009	Ankara	Infants 12 months of age	Laboratory-based	23.5%	n.r	n.r	Male: 22.6% Female: 24.5%	n.r
Hendrickx et al.^Citation28	November – December 2007	National	n.r	Meeting report	71.3% (2002)	Seroprevalence increased at school age (5–9 YOA) with peak in late adolescence (20–24 YOA) By 10 YOA: 50% anti-HAV positive	n.r	n.r	n.r
Coskun et al.^Citation73	1998–2007	Eskisehir	Average 19.5 YOA	Hospital-based	HAV IgG positive: 1998–2002: 42.0% 2003–2007: 54.0%; p < .001	n.r	n.r	n.r	n.r
Ceyhan et al.^Citation50	June 2005 – May 2006	South-Eastern Anatolia, Marmara, central Anatolia, Aegean, and Eastern Anatolia regions	1 month-91 YOA	Hospital-based (inpatient)	64.4%	5–9 YOA: >80.0% 15–19 YOA: >90.0% (south-eastern and eastern regions)	5–9 YOA: Central Anatolia: 34.0%; Aegean: 36.0%; Marmara: 44.0%	n.r	n.r
Kaya et al.^Citation74	September – December 2005	Kahramanmaras	6 months-18 YOA	Cross-sectional survey	57.2%	6-23 months: 35.5% 2-5 YOA: 19.2% 6-10 YOA: 74.3% 11-14 YOA: 83.0% 15-18 YOA: 92.8%; p < .001	n.r	Male: 59.5% Female: 54.7%	Children with two or less siblings: 37.5% 3–5 siblings: 68.3% > 6 siblings: 81.2% in children; p < .001 Paternal education Illiterate: 65.7% Literate: 67.4% Primary school graduates: 59.0% Junior high school graduates: 53.6% High school graduates: 53.8% College graduates, 50.0%; p > .05 Maternal education Illiterate: 76.1% Literate: 65.7% Primary school graduates: 53.6% Junior high school graduates, 57.3% High school graduates, 38.7% College graduates, 11.8%; p < .001 Living conditions ≤4 people in household: 39.0% 5–6 people in household: 63.3% >7 people in household: 74.7%
Kaya et al.^Citation75	April – June 2003	Duzce	6 months-17 YOA	Prospective laboratory-based	63.8%	6 months-5.9 YOA: 28.8% 6.0–12.9 YOA: 79.0% 13.0–17.0 YOA: 76.8%; p < .01	n.r	n.r
Atabek et al.^Citation62	2001–2002	Konya	1–18 YOA	Cross-sectional survey	70.0%	1–6 YOA: 45.7% 7–12 YOA: 64.3% 13–18 YOA: 93.5% Rural areas: 1–6 YOA: 67.8% 7–12 YOA: 91.4% 13–18 YOA: 97.2% Urban areas: 1–6 YOA: 25.7% 7–12 YOA: 39.4% 13–18 YOA: 90.8% rural versus urban (p < .0001)	n.r	Rural areas: Male: 45.0% Female: 42.0% Urban areas: Male: 29.0% Female: 25.4% p < .0001	Urban areas: 54.4% Rural areas: 87.0% Low socioeconomic level: 73.0% Middle to high socioeconomic level: 27.0%; p = .001
Sac et al.^Citation56	August – September 2002	Ankara	1–15 YOA	Prospective cross-sectional hospital-based (outpatient)	HAV IgG positive: 47.2% HAV IgM positive: 15.5%	HAV IgG positive 1–2 YOA: 34.1% 3–5 YOA: 23.1% 6–10 YOA: 48.9% 11–15 YOA: 69.4% HAV IgM positive 1–2 YOA: 0.0% 3–5 YOA: 12.3% 6–10 YOA: 22.7% 11–15 YOA: 14.1%	n.r	Male: 43.2% Female: 51.6%	n.r
Tosun et al.^Citation76	January 2000 – June 2001	Manisa	6 months – 17 YOA	Laboratory-based	44.6%	6–23 months: 47.8% 2–6 YOA: 23.7% 7–10 YOA: 43.4% 11–14 YOA: 52.4% 15–17 YOA: 76.6%; p < .0001 HAV positivity in relation to socioeconomic level middle or high: 6–23 months: 33.8% 2–6 YOA: 31.5% 7–10 YOA: 35.2% 11–14 YOA: 38.2% 15–17 YOA: 30.6%; p < .0001 Low socioeconomic level: 6–23 months: 66.2% 2–6 YOA: 68.5% 7–10 YOA: 64.8% 11–14 YOA: 61.3% 15–17 YOA: 69.4%; p < .0001	n.r	n.r	Middle or high socioeconomic level: 48.8% Low socioeconomic level: 51.2%
Kanra et al.^Citation77	n.r	All regions	Subjects <30 YOA	n.r	71.3%	1 YOA: 42.7% 25–29 YOA: 91.1% By 10 YOA: 50.0%	n.r	Male: 69.3% Female: 73.0%	≥6 people in household: 80.1% <6 people in household: 66.7%
Sidal et al.^Citation78	June 1997 – June 1998	Istanbul	6 months-15 YOA	Laboratory-based	Anti-HAV IgG 29.5%	6 months-2 YOA: 12.2% >2 YOA: 18.6% 6.0 months-4.9 YOA: 15.1% 5.0–9.9 YOA: 26.7% 10.0–15.0 YOA: 49.6%; p < .05	n.r	n.r	n.r
Ersoy et al.^Citation55	n.r	n.r	6 months-16 YOA	Hospital-based (outpatient)	n.r	0–4 YOA: 7.81% 5–8 YOA: 39.0% 13–16 YOA: 68.0%; p < .05 High socioeconomic level: 5–8 YOA 10.24%	n.r	n.r	n.r
Baki et al.^Citation49	August to September 1991	Trabzon	6 months-18 YOA	Laboratory-based	Average: 47.0% Range: 13.4%–88.6%	6 months-3 YOA: 13.4% 4–7 YOA: 32.1% 8−12 YOA: 63.4% 13–18 YOA: 88.6%	n.r	n.r	n.r

HAV, hepatitis A virus; IgG, immunoglobulin G; IgM, immunoglobulin M; n.r, not reported; YOA, years of age.

Noting these findings, it is important to consider the heterogeneity of findings in the different regions of Turkey. A strong West-East gradient is evident when observing HAV seroprevalence rates (Table 2). For example, one study shows that highly endemic regions in the Eastern and South-Eastern parts of the country have incidences of up to 23.6 per 100,000 whereas an average incidence rate of 10 per 100,000 has been documented in the intermediate endemic Western regions.⁵⁵

Besides age- and region-specific heterogeneities, the studies reveal important general trends. Notable differences in the hepatitis A endemicity profiles between urban and rural areas were documented in Turkey. In one study, it was found that less than one-third of children below 6 YOA living in urban areas had immunity.⁵⁶ Other studies conducted in Turkey demonstrated that living in crowded conditions, having a high number of siblings, and being part of a household with low income and education level (maternal and paternal) were risk factors for HAV exposure and transmission for children (Table 2). There is little evidence to support any true differences in HAV seroprevalence by gender, revealing that both males and females have nearly equivalent levels of HAV exposure, and no seroprevalence data were found by nationality. Two studies investigated HAV seroprevalence in adult patients with chronic viral hepatitis and chronic liver disease, respectively. In these patients, high HAV seropositivity was documented (>90%), with a higher HAV seroprevalence observed with increasing age.^57,58 (Table 2).

An expanded government-funded program on immunization for children, including hepatitis A immunization, has been implemented in Turkey since October 2012. Hepatitis A vaccine is administered to children in two doses at 18 and 24 months of age.⁵⁹ Three inactivated hepatitis A vaccines have been licensed for use: Havrix (GSK), VAQTA (MSD), and Healive (Sinovac). The national hepatitis A immunization program of Turkey appears to have been highly effective in reducing further HAV cases (Figure 2(a)). After the introduction of hepatitis A vaccination in Turkey, the incidence of hepatitis A saw a much more pronounced decline compared to the reduction documented before the implementation of childhood hepatitis A vaccination across individuals of all ages with suggestive herd protection effects.⁵⁰ However, since the implementation of vaccination in 2012, the trend in age-specific incidence of HAV reveals only a slight shift in the occurrence of HAV cases from very young children to older children, adolescents and young adults (Figure 2(b)). Reductions in HAV incidence are seen shortly after vaccine implementation, and also in age groups not targeted by the vaccine (Figure 2(b)). According to data from 2017, a downward trend in the incidence of hepatitis A was seen across all the regions of Turkey (Figure 2(c)).

Figure 2. Burden of HAV disease in Turkey (a) Number of hepatitis A cases (b) Age-specific incidence of hepatitis A (c) Regional incidence of hepatitis A

Source: Ministry of Health, Turkey²⁴* Implementation of childhood hepatitis A vaccination in the Turkish UMV. HAV, hepatitis A virus; UMV, universal mass vaccination; YOA, years of age.

Discussion

A large proportion of the population of the MENA region is living in low- and middle-income countries and is faced with viral hepatitis A as a major public health problem, especially those transitioning from high to intermediate HAV endemicity.^19,20,22 Most of the countries in this region have a high endemicity of HAV infection and several countries are stipulated to be transitioning from high to intermediate endemicity.^19,20,22 The epidemiological shift of infection burden from children to adults could lead to an increase in health-care costs. Given the recent and rapid socioeconomic developments in this region, determining the epidemiological pattern of HAV infection has become crucial for health-care policymakers to make informed decisions about implementing cost-effective disease management strategies. In this review, we describe the epidemiology and seroprevalence of HAV from two countries in the MENA region that have had several years of experience with a childhood hepatitis A vaccination program. In choosing these two countries as examples, we expect the findings to be largely applicable to the majority of the nations in the MENA region. Saudi Arabia can be considered representative of the transitioning countries in the MENA region, whereas Turkey can be considered representative of upper-middle-income nations in the MENA region, given its heterogeneity with common socioeconomic and health-care indicators observed across the different regions of Turkey (income levels, access to safe water and adequate sanitation facilities, urbanization, unemployment, inflation, the density of housing, living conditions and immunization services, migration patterns, among others).

In the last few decades, HAV epidemiology has changed in Saudi Arabia and Turkey, from a high to an intermediate endemicity pattern, whereby the average age of HAV infection has been increasing. This shift has been a well-known epidemiological feature worldwide in countries that have seen improvements in public health-care policies, sanitation, and education.^7–9,11,13 Furthermore, childhood vaccination programs were implemented in Saudi Arabia and Turkey in 2008 and 2012, respectively. Large declines in HAV disease burden have been seen in both countries with the shift in age groups becoming more pronounced, leaving adolescents and young adults susceptible to HAV. This is concerning because with increasing age, the risk of developing symptomatic disease and severe clinical manifestations also increases. Additionally, in these regions where a substantial proportion of adolescents and adults is susceptible, HAV may circulate, often through regular community-wide outbreaks. Thus, paradoxically, with the transition from high to intermediate endemicity, the incidence of clinically significant hepatitis A increases.

The changes in epidemiology and disease burden observed across the different regions of Saudi Arabia seem to be homogeneous as compared to those seen in Turkey. Regardless, important differences merit further discussion. In Saudi Arabia, although a general pronounced decrease in HAV incidence is seen after the implementation of childhood hepatitis A vaccination, a significant increase in the total number of hepatitis A cases was documented around 2018; specifically, an increase in hepatitis A cases among individuals of 15–44 YOA and ≥45 YOA. To avoid a further increase in cases and the occurrence of outbreaks, it is recommended to implement measures to ensure high vaccination coverage of hepatitis A vaccination is maintained among children. In addition, awareness programs about hepatitis A should be implemented for the general population. In contrast, the situation in Turkey depicts that older children, adolescents, and young adults remain susceptible to HAV infection. Turkey is characterized by marked regional differences in HAV endemicity – levels are high in Eastern regions, while Western Turkey shows only intermediate endemicity.⁵⁵ Moreover, the high level of HAV seroprevalence reported in marginalized populations, especially those living in the rural areas of Turkey, presents an important public health issue as a relatively large proportion of young adults are susceptible to infection. This can be explained by the depleting quality of water resources in the river basins of the Eastern region of Turkey (covering Ceyhan, Asi, and Southeast part of Firat-Dicle), due to the uncontrolled human-induced activities which have led to the deterioration of the environmental performance indicators representing environmental stressors.⁶⁰ Alternatively, internal and external migration patterns pertinent to Turkey have also been documented as a reason for such heterogeneous findings across the regions of Turkey. More people originating from highly endemic regions in Eastern Turkey are moving to the Western regions of the country, residing along susceptible second generations and who also travel back to the high-endemicity home regions during holidays.^55,61 Migration of individuals from highly endemic conflict areas, such as Syria, Lebanon and Iraq could also be the reason for HAV transmission to susceptible individuals in Turkey and may have led to localized outbreaks in Turkish communities.^60,62,63 The burden of symptomatic disease must be addressed further to support specific programs of continued sanitation and education improvement and the possibility of vaccination in more susceptible regions. As a consequence, the general population of Turkey is at risk of HAV infection, mainly due to the high level of migration from the East to the West region of the country and migration into the rural areas from surrounding conflicted areas (Syria and Iraq) in the MENA region.

The childhood hepatitis A vaccination program in Turkey has been successful in reducing the burden of disease in children, with the potential to demonstrate herd immunity effects as indicated by reductions in HAV incidence seen in age groups not targeted by the vaccine. This finding could be relevant for the MENA region as it has been established that herd immunity effects more than doubled the savings from hepatitis A immunization during the first 10 years of the program.⁶⁴ Whether this will truly be the case for the Turkish program is still to be determined. In the context of herd immunity, high vaccination coverage in the target vaccination group in Turkey is the need of the hour. Moreover, a strengthened health surveillance system, nationwide serological surveys and tracking rate of childhood vaccination uptake will be valuable for monitoring the evolving HAV epidemiology in Turkey.

This narrative review has several limitations related to the methodology, such as the lack of a systematic approach to identify relevant literature and the inclusion of gray literature sources (i.e., literature not peer-reviewed prior to publication, such as government databases, websites, and reports) in the search. However, we found this methodology appropriate given the limited geographic scope of this review. Generalizability of the results from this review to other countries in the region may be hindered due to the different health systems in the region, the difference in reporting systems, and in case definitions. In addition, a lack of published impact of vaccination data from Saudi Arabia and Turkey limited comparison with data from before the childhood immunization program was implemented. Furthermore, while seroprevalence data and inferences about endemicity shifts are based on IgG measurements, some studies only report the total Ig (IgM+IgG). This is an important caveat in any interpretation on the endemicity shift from the available seroprevalence data. When reporting IgG levels, most studies do not distinguish between vaccine-induced IgG and infection-induced IgG. Techniques to differentiate the origin of acquired immunity have been developed,⁷⁹ but may not be widely used, yet if used in future studies, could be important for public health decisions and planning. Generalizability of the data from this review to the region might be limited due to a lack of data on outbreaks in the literature for both countries; possible reasons for this could be the review methodology or the fact that these data are generally lacking. Nonetheless, these data are essential to ascertain and confirm a HAV endemicity shift from high to intermediate in the region (Figure 3). Finally, data on the economic burden attributable to the endemicity shift in the region albeit lacking would be helpful to make informed decisions about disease management strategies.

Figure 3. Plain language summary

Conclusions

In Saudi Arabia and Turkey, the burden of HAV has decreased in the overall population and this is attributable to socioeconomic improvements and the implementation of a childhood hepatitis A vaccination program; nonetheless, older children continue to be affected in Turkey and an increasing number of adolescents and adults is being primarily affected by the disease in both countries. Published data on vaccination impact from both countries are lacking and therefore reliable epidemiological data from large cross-sectional observational studies are urgently needed to ensure that existing strategies to control HAV in the region are revisited and updated in time. Across regions that are still struggling with poor living conditions and access to clean and safe drinking water, efforts are urgently needed to ensure the supply of clean, safe water, and adequate sanitation facilities. Continuing the childhood hepatitis A vaccination program in both Saudi Arabia and Turkey remains beneficial considering the intermediate endemicity level, however, depending on the evolving epidemiology in the region, potential interim solutions, such as hepatitis A vaccination of adolescents and adults, including those with an underlying comorbidity, might be needed for the effective control and prevention of HAV exposure of these susceptible population groups. Building on the experience of Saudi Arabia and Turkey with childhood hepatitis A vaccination, countries in the MENA region can use these findings to support discussions on potential vaccination strategies suitable for their own countries.

Contributorship

Selim Badur, Serdar Öztürk, Mansour Khalaf, and Debasish Saha contributed to the study design. Selim Badur, Serdar Öztürk, Alev Ozakay and Mansour Khalaf performed the literature search. Selim Badur, Serdar Öztürk, Alev Ozakay, and Debasish Saha provided materials or tools for the analysis. Selim Badur performed the analysis. Selim Badur, Serdar Öztürk, Alev Ozakay, Debasish Saha, and Pierre Van Damme interpreted the results. All authors participated to the development of this manuscript. All authors had full access to the data and gave final approval before submission.

Trademark

Avaxim is a trademark owned by or licensed to Sanofi Pasteur. Havrix is a trademark owned by or licensed to the GSK group of companies. Healive is a trademark owned by or licensed to Sinovac Biotech Ltd. VAQTA is a trademark owned by or licensed to Merck & Co.

Disclosure of potential conflicts of interest

Selim Badur, Serdar Öztürk, Alev Ozakay, Mansour Khalafand Debasish Saha are employees and shareholders of the GSK group of companies. Pierre Van Damme declares no personal financial conflicts of interest, and reports grants to his institute, the University of Antwerp, from the GSK group of companies, Pfizer, Sanofi, Merck, Takeda, Baxter, CanSino China, Themis, Osivax, J&J and Abbott, and grants from The Bill & Melinda Gates Foundation, PATH, the Flemish government, and the European Union, outside the submitted work. Selim Badur, Serdar Öztürk, Alev Ozakay, Mansour Khalaf, Debasish Saha and Pierre Van Damme declare no other financial and non-financial relationships and activities.

Acknowledgments

The authors thank Business & Decision Life Sciences platform for editorial assistance and manuscript coordination on behalf of GSK. Amandine Radziejwoski coordinated the manuscript development and editorial support. Amrita Ostawal (Arete Communication UG, on behalf of GSK) provided medical writing support.

Additional information

Funding

GlaxoSmithKline Biologicals SA funded this study and was involved in all stages of study conduct, including analysis of the data. GlaxoSmithKline Biologicals SA also paid all costs associated with the development and publication of this manuscript.