A Call for Adopting High-Dose Influenza Vaccines for Adults Aged 65 and Above in Gulf Cooperation Council (GCC) Countries

Abstract

Seasonal influenza poses significant health and economic challenges globally each year, particularly impacting the elderly population (aged ≥ 65 years) with increased rates of hospitalization, and mortality. The population of older adults is steadily increasing in the Gulf Cooperation Council (GCC) countries and is likely to increase even further. In addition, there is a high burden of chronic comorbidities in these countries like diabetes and obesity, which increases the likelihood of severe consequences of influenza infection. The GCC countries also host mass gathering events like Hajj, Umrah pilgrimage, Arba’een (nearby Iraq) pilgrimage, and international sports and business events, which further intensify the risk of outbreaks like influenza. These events facilitate the mixing of visitors from various countries. Thus, influenza activity in this North Hemisphere (NH) geography is usually present even before the availability of NH seasonal influenza vaccine. This is especially problematic for the elderly, whose protection from the previous year’s immunization would have waned. Higher dosages of antigens or adjuvants have been used to improve immunogenicity in older people with superior vaccine effectiveness. Therefore, there is a compelling argument in favor of the implementation of high-dose seasonal influenza vaccines in the GCC countries to improve the protection of individuals aged 65 years and older against influenza infection and associated severe complications.

Introduction

Each year, seasonal influenza causes a significant health and economic burden on global public health. Globally, an estimated 290,000 to 650,000 people die each year from influenza-related respiratory complications, and the virus infects 5–20% of the population, making it a leading cause of morbidity and mortality [1]. Furthermore, it ranks among the top 10 major risks to global public health [2]. Certain population groups are at high risk for severe illness, hospitalization, and death, including young children, adults aged ≥ 65 years, pregnant women, and those with underlying comorbidities [3]. The vast majority of influenza hospitalizations (50–70%) and deaths (70–85%) occur among individuals 65 years of age and older [4].

Annual seasonal influenza vaccination is the most effective way of preventing influenza illness, reducing the incidence of moderate-to-severe illness and hospitalization, and decreasing transmission of the influenza virus [4]. Despite the endorsement of international guidelines for adults aged 65 and above, constituting a high-risk group for influenza complications, vaccination uptake remains inadequate in most countries around the world, with the majority of countries exhibiting vaccination rates significantly below the 75% threshold set forth by the World Health Organization (WHO) for this age group [5].

Data regarding overall uptake of influenza vaccine are scant in the Gulf Cooperation Council (GCC) countries. The influenza vaccination rate (IVR) has been reported as 31.8% in Saudi Arabia in 2022 [6]. Moreover, due to the impact of the Coronavirus disease 2019 (COVID-19) pandemic on public perceptions of seasonal influenza being of mild nature, GCC countries have reported a decrease in the use of influenza vaccinations [7].

Seasonal Influenza Immunization and Efficacy/Effectiveness of High-dose Influenza Vaccine in Older Adults

The burden of influenza and influenza-related complications is much higher in older adults (≥ 65 years) owing to immunosenescence, frailty, and existing comorbidities. Furthermore, ineffective recall responses and a progressive decline in influenza-specific antibody production are common with aging [8], resulting in reduced immunogenicity and effectiveness of the vaccine in this age group. A meta-analysis indicated that the influenza vaccine effectiveness in reducing hospitalization was only 37% in adults over 65 year’s old [9].

During the 2022–23 influenza season in the US, vaccine effectiveness (VE) against influenza-associated hospitalization was 28% among those aged 65 years or older, compared to 47% among adults aged 18–64 years. Moreover, studies have also consistently shown that VE is lower for influenza A (H3N2) than for influenza A (H1N1) pdm09 and type B viruses for those ≥ 65 years [10].

The inclusion of higher doses of antigens is one of the strategies adopted to enhance the immunogenicity and effectiveness of influenza vaccines in older adults. A large phase IIIB-IV double-blinded, randomized controlled trial, performed during the 2011–2012 and the 2012–2013 Northern Hemisphere influenza seasons and involved 31989 adults ≥ 65 years of age from 126 centers in the US and Canada; compared a high-dose, trivalent, inactivated influenza vaccine (HD-IIV3) (60 µg of hemagglutinin per strain) with a standard-dose vaccine (SD-IIV3 [15 µg of hemagglutinin per strain]), in terms of relative efficacy, effectiveness, safety, and immunogenicity [HAI] titers). The study revealed that the HD-IIV3 induced significantly higher antibody responses and provided better protection against laboratory-confirmed influenza illness than did SD-IIV3. The overall efficacy of 24.2% against the primary endpoint indicates that about one quarter of all breakthrough influenza illnesses could be prevented if HD-IIV3 is used instead of SD-IIV3 [11].

Similarly, studies have reported that the HD-IIV3 vaccine conferred a greater protection against laboratory-confirmed influenza than the SD-IIV3 vaccine among middle-aged adults between the ages of 50 and 64 as well as those over the age of 65 [8, 9]. A meta-analysis of 7 studies in older adults involving more than 41,000 patients showed that the HD-IIV3 was well-tolerated, more immunogenic, and more efficacious in preventing influenza infections than the standard-dose vaccine, with significantly less risk of developing laboratory-confirmed influenza infections in patients receiving the high-dose vaccine (Relative Risk 0.76) [12]. In a recent systematic review of studies conducted over 12 influenza seasons (2009/2010 to 2019/2020, 2021/2022) that involved over 45 million individuals aged ≥ 65 years, HD-IIV3 provided significantly better protection than SD-IIV3 against influenza-like illness, influenza-related hospitalizations, as well as cardiovascular, cardiorespiratory, and all-cause hospitalizations. HD-IIV3 consistently provided better protection than SD-IIV3 against influenza outcomes across the age range (65+, 75 + 85 + years) regardless of the predominantly circulating influenza strain and vaccine antigenic match/mismatch [13].

HD-IIV3 triggers a superior immune response compared to the SD-IIV3 due to a higher dose of the antigen in the former. HD-IIV3 recipients aged 65 years and above were much better protected against influenza, with a relative vaccine efficacy (rVE) of 24.2% [14]. In Japan, Sanchez et al. recently demonstrated that HD-IIV4 provided superior immunogenicity when compared to SD-IIV4 in participant’s ≥ 60 years of age [15].

Quadrivalent vaccines have been shown to confer extra protection due to the additional B strain in the quadrivalent influenza vaccine (QIV) when compared to the trivalent influenza vaccines (TIV). However, the WHO has recently recommended that there should be a transition back to trivalent vaccines (Influenza A/H1N1, A/H3N2, and B/Victoria strains) given the global disappearance of B/Yamagata since the onset of the COVID-19 pandemic [14].

The Influenza Disease Burden in the Gulf Cooperation Council (GCC) Countries among Age Group > 60 Years Old

Studies regarding the burden of influenza among the older population is very scarce in the GCC highlighting the urgent need for such data to inform local vaccination policies. One study from Oman reported that the incidence of influenza-associated SARI was highest among the 0–4 year old age group (range 32–42 cases per 100,000 population) followed by the 65 + age group (12–27 occurrences per 100,000 population) [16].The highest incidence of influenza-associated death was among those aged ≥ 65 years and ranged between 39.5 per 100 000 in 2014 and 11.3 in 2015 [17].

Scope of Year-round Protection against Influenza in the Gulf Cooperation Council (GCC) Countries

The GCC countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates) are considered travel hubs connecting the western and eastern parts of the world as well as being the host of various mass gathering events (e.g., Hajj, Umrah, and Arba’een (nearby Iraq) pilgrimages) [18–19] and international sports and business events. This increase the risks of outbreaks of communicable diseases, including influenza [20]. In addition, due to consistently high humidity and temperatures, these countries, similar tropical regions, experience waves of influenza activity throughout the year compared to the usual seasonal transmission during cooler months in countries with temperate climates [21].

The intermixing of travelers, including pilgrims, coming from geographical areas with diverse influenza circulation patterns and different transmission zones contributes to the year-round transmission of influenza. This means that influenza activity may start before the seasonal influenza vaccine for the Northern Hemisphere becomes available, which is particularly concerning for the older population, whose protection from the previous year’s vaccination would have significantly waned at the time of onset of this activity. This emphasizes the need for modifying vaccination strategies for this high-risk population in terms of the timing of influenza vaccination campaigns in GCC countries and to include both the Southern and Northern Hemispheres’ vaccine compositions.

Population Aging in GCC Countries and the Case for HD-influenza Vaccine

Influenza vaccination is recommended to all high-risk population groups in all GCC countries in the national influenza vaccination policies. According to the policies, all high-risk population groups are offered the influenza vaccine at no cost by primary health care providers [personal communications].

On a global scale, life expectancy is increasing while birth rates are declining, contributing to demographic shifts toward elderly populations. The GCC countries are witnessing a similar trend, with projections indicating an increase in the proportion of individuals aged 50 and above from 14.2% in 2020 to 18.5% by 2025. In addition, it is anticipated that the population of the GCC countries will age considerably by the end of this century, with an overall older population as the median age increases from 32 years in 2022 to 51 years in 2100 [22]. Moreover, the GCC countries currently have the highest rates of chronic diseases, including but not limited to diabetes and obesity, which are known to increase the risk of severe outcomes with influenza infection [7, 23].

It is crucial to protect this population aged ≥ 65 years in the GCC countries from influenza and its severe complications by providing access to more effective influenza vaccines, aligning with the general guidelines by independent health authorities (e.g., US CDC, German STIKO, Canadian NACI, etc.). Given the rich and high-quality evidence regarding the higher effectiveness of HD-IIV, making it available for the aged population in the GCC countries is a wise public health choice.

In January 2024, Saudi Arabia became the first country in the region to introduce the seasonal HD-IIV to adults aged 65 and older [personal communication].

Against the backdrop of an aging population with several comorbidities, there is clearly a need to enhance this population’s protection from influenza and its potential complications. Given the fact that older adults fail to mount and sustain an optimal and durable antibody response in response to standard flu vaccines, [24] it is strongly advised to consider adopting strategies to enhance the protective antibody response to vaccination through the use of HD-IIV. Even as robust economic cushion of the GCC countries may allow high dose influenza vaccination to be adopted as a strategy by the various National Immunization Programs of the GCC countries with public funding, the overall high health and economic burden of influenza and its complications would strongly argue in favor of this strategy as a potentially net cost effective one.

Conclusions

There is a strong case for introducing the HD-IIV in the GCC countries to enhance protection against influenza infection and severe complications among adults ≥ 65 years old. The highest quality evidence from RCTs and pragmatic randomized trials must form the basis of national recommendations. Regional studies regarding the safety and effectiveness of the HD-IIV vaccines in specific risk groups, along with their cost-effectiveness should be undertaken in order to inform public health policy. Strong advocacy campaigns and easy access programs should accompany the revision of vaccination policies and guidelines for including HD-IIV in the national immunization programs to ensure adequate uptake among this population.

Abbreviations

WHO

World Health Organization

GCC

Gulf Cooperation Council

IVR

Influenza vaccination rate

COVID-19

Coronavirus disease 2019

VE

Vaccine effectiveness

RCTs

Randomized clinical trials

HD-IIV3

High-dose inactivated influenza vaccine 3

SD-IIV3

Standard dose trivalent vaccine3

Author Contributions

S.A, P.K., F.K.,F., S., I.J.F.A., K.E., M.A., F.O., M.T. and H.Z contributed to the study concept and design. S.A, P.K., F.K.,F.,S., I.J.F.A.,K.E., M.A., F.O., M.T. and H.Z collected and assembled the data S.A, P.K., F.K.,F.,S., I.J.F.A.,K.E., M.A.,F.O.,M.T. and H.Z drafted the manuscript. S.A, P.K., F.K., and H.Z. critically revised the manuscript for important intellectual content. All authors have read and agreed to the published version of the manuscript.

Funding

Not applicable.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Ethics Approval and Consent to Participate

Not applicable.

Consent for Publication

Approved.

Competing Interests

The authors declare no competing interests.

Informed Consent

Not applicable.