Novel vaccine strategies to improve responses in the eldelry

As explained earlier in the weblog, the immune system changes when we get older. The ability to maintain memory responses for over extended periods of time decreases, which leads to more rapid decline of antibody levels. Consequently, the immune responses to vaccines in the elderly are substantially lower. This presents us with a challenge in our society to prevent infectious diseases. Using vaccinations is the most cost-effective, easy and safe option to inhibit infectious diseases among the aged. Extensive research has already been done to increase vaccine-induced immune responses among the elderly, but there is not just one solution. In this blog, we will discuss several methods to enhance vaccine responses in the elderly that have been already implemented or are being tested.

Case study: adjuvanted influenza vaccines

As an example, one of the most significant vaccine challenges among the elderly is the influenza vaccine. Influenza is a very common and contagious disease. The most hospitalizations and deaths due to influenza occur among the elderly [1]. There are more than 500.000 deaths each year, caused by the influenza virus, reported in people aged above 65 years [2]. 

1. Higher antigen dose

One approach is to give a higher antigen dose within the vaccine. It has been shown in several studies on multiple vaccines that the use of a higher antigen dose gives more protective antibody response [3]. For the influenza vaccine, the administration of a higher antigen dose is proven to be effective in creating a better immune response in the elderly [1].

2. Adjuvants 

Secondly, it is possible to add more immunogenic adjuvants to the vaccinations. 

Adjuvants are substances which are added to vaccines to improve the immune response [3]. 

Aluminum salts are commonly used adjuvants, but they are often not sufficient enough to create a high immune response in the elderly. There are several studies being done to test the efficiency of aluminum salts as adjuvants. Some said they were beneficial, some proved no benefits and others proved that it was disadvantageous [4]. This shows that much is still unknown about the use of adjuvants, so ongoing research is needed for improving vaccine efficacy. 

For example, for the influenza vaccine the adjuvant MF59 has proved to work very well. The adjuvanted influenza vaccine is now already used in some European countries, such as Austria and the UK. The first season the adjuvanted vaccinations were used, the protection of the elderly people was higher than the years before [5]. Less people were hospitalized for pneumonia. MF59 is an immunological adjuvant that has been added to the influenza vaccine. MF59 increases the antigen uptake and presentation, which improves the immune response against the virus. Several studies [4] have demonstrated a higher antibody production after the adjuvanted influenza vaccine. 

Shingrix is the varicella-zoster vaccine, which prevents against the herpes virus. There is an adjuvanted variant of the vaccine, called HZ/su, which significantly reduced the risk of herpes zoster in adults above the age of 50 years old [6]. 

3. Booster injections

Thirdly, administering booster injections to the elderly can trigger memory B- and T-cells, enabling a quicker and stronger response for a next exposure to the infection. We have seen this strategy with the COVID-19 vaccine. 

For example, there has been a study done to evaluate the effectiveness of annual influenza booster vaccinations among people aged 64 years and older [7]. The data support that giving an annual influenza vaccination causes a significant decrease in influenza-associated hospitalizations. 

4. Alternative routes of vaccine administration 

The fourth strategy to improve vaccine responses is to use alternative routes of vaccine administration. Traditionally, we use percutaneous injections, such as subcutaneous and intramuscular. Recent developments in microinjection techniques have introduced the intradermal route. With intradermal administration the antigen is presented directly in the skin. The skin contains a lot of immune cells that are available to present the antigens. They will activate the T-cells and the immune response is initiated. The intradermal vaccination technique causes a mucosal and systemic immune response, involving Langerhans cells [8].

In elderly people there are changes in the skin, such as the vasculature, which should be considered using the intradermal technique. 

Another route can be mucosal administration of vaccinations. This is especially a good route for infections such as influenza and pneumonia. The antigen presenting cells in the mucosa will activate the immune response. The research that has been done on this administration route is still very limited, so that can be an important field of study for the future. 

5. Timing of vaccine administration

Furthermore, we can adjust the vaccine injection time. This means the time of the day when you administer the vaccination can impact the immune response. Our immune system is affected by circadian rhythms. In a population based study [9] the effect of the time of day of administration of the COVID-19 vaccine has been investigated. As seen in the figure below, morning administration (09:00 - 10:00) had the highest antibody levels, early afternoon (12:00 - 13:00) the lowest and late afternoon (14:00 - 15:00) had intermediate antibody levels. The study shows that administration in the morning is better than the afternoon for the immune response. This can be relevant for vaccine strategies in the elderly, because higher antibody levels can be reached with minimal changes. 

Figure 2. Note. Erber AC, Wagner A, Karachaliou M, Jeleff M, Kalafatis P, Kogevinas M, Pepłońska B, Santonja I, Schernhammer E, Stockinger H, Straif K, Wiedermann U, Waldhör T, Papantoniou K. The Association of Time of Day of ChAdOx1 nCoV-19 Vaccine Administration With SARS-CoV-2 Anti-Spike IgG Antibody Levels: An Exploratory Observational Study. J Biol Rhythms. 2023 Feb;38(1):98-108. doi: 10.1177/07487304221132355. Epub 2022 Nov 11. PMID: 36367167; PMCID: PMC9659693.

6. Senolytic and immunomodulatory drugs

Another hypothetical option is to give senolytic or immunomodulatory drugs to the elderly. Cellular senescence means that cells have a growth stop when we get exposed to stressful stimuli [10]. As a consequence, pro-inflammatory responses are induced and B-cells have several defects. This results in a lower immune response to vaccines, especially in the elderly. Senolytic drugs can remove these harmful senescent cells, which will stop the inflammation. 

The COVID-19 pandemic has brought new light to the vaccination development. mRNA vaccines were used to prevent COVID-19 and they turned out to have high efficacy in the older population [3]. One of the reasons for the high efficacy is that RNA can be detected by multiple receptors that lead to the production of cytokines and chemokines. This again leads to the activation of antigen-presenting cells that go to the site of infection. Furthermore, mRNA vaccines have an enhanced antigen expression in comparison to standard vaccinations. The disadvantage of the COVID-19 vaccines is that there is rapid waning of the efficacy of the vaccine. 

Conclusion

Enhancing vaccine responses among the elderly is very important in considering the prevention of infectious diseases. There is not just one solution for all vaccines, so a multifaceted approach is needed. Several strategies can be combined, as discussed before. These include higher antigen doses, using adjuvants, boosters, alternative routes of administration, timing and senolytic drugs. For improving the immune responses for the influenza vaccine, some of these strategies already have proved to be efficient. The adjuvanted influenza vaccine with MF59 resulted in less influenza-associated hospitalizations. Ongoing research will be needed to improve these strategies, but implementation has already proved to be successful in some cases. 

Literature

1. Bell MR, Kutzler MA. An old problem with new solutions: Strategies to improve vaccine efficacy in the elderly. Adv Drug Deliv Rev. 2022 Apr;183:114175. doi: 10.1016/j.addr.2022.114175. Epub 2022 Feb 22. PMID: 35202770.

2. Bulut O, Kilic G, Domínguez-Andrés J, Netea MG. Overcoming immune dysfunction in the elderly: trained immunity as a novel approach. Int Immunol. 2020 Nov 23;32(12):741-753. doi: 10.1093/intimm/dxaa052. PMID: 32766848; PMCID: PMC7680842.

3. Soegiarto G, Purnomosari D. Challenges in the Vaccination of the Elderly and Strategies for Improvement. Pathophysiology. 2023; 30(2):155-173. https://doi.org/10.3390/pathophysiology30020014. 

4. Lefebvre JS, Haynes L. Vaccine strategies to enhance immune responses in the aged. Curr Opin Immunol. 2013 Aug;25(4):523-8. doi: 10.1016/j.coi.2013.05.014. Epub 2013 Jun 10. PMID: 23764092; PMCID: PMC3775954.

5. Pereira B, Xu XN, Akbar AN. Targeting Inflammation and Immunosenescence to Improve Vaccine Responses in the Elderly. Front Immunol. 2020 Oct 14;11:583019. doi: 10.3389/fimmu.2020.583019. PMID: 33178213; PMCID: PMC7592394. 

6. Lal H, Cunningham AL, Godeaux O, Chlibek R, Diez-Domingo J, Hwang SJ, Levin MJ, McElhaney JE, Poder A, Puig-Barberà J, Vesikari T, Watanabe D, Weckx L, Zahaf T, Heineman TC; ZOE-50 Study Group. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med. 2015 May 28;372(22):2087-96. doi: 10.1056/NEJMoa1501184. Epub 2015 Apr 28. PMID: 25916341.

7. Hsu PS, Lian IB, Chao DY. A Population-Based Propensity Score-Matched Study to Assess the Impact of Repeated Vaccination on Vaccine Effectiveness for Influenza-Associated Hospitalization Among the Elderly. Clin Interv Aging. 2020 Mar 3;15:301-312. doi: 10.2147/CIA.S238786. PMID: 32184579; PMCID: PMC7060795.

8. Criscuolo E, Caputo V, Diotti RA, Sautto GA, Kirchenbaum GA, Clementi N. Alternative Methods of Vaccine Delivery: An Overview of Edible and Intradermal Vaccines. J Immunol Res. 2019 Mar 4;2019:8303648. doi: 10.1155/2019/8303648. PMID: 30949518; PMCID: PMC6425294.

9. Erber AC, Wagner A, Karachaliou M, Jeleff M, Kalafatis P, Kogevinas M, Pepłońska B, Santonja I, Schernhammer E, Stockinger H, Straif K, Wiedermann U, Waldhör T, Papantoniou K. The Association of Time of Day of ChAdOx1 nCoV-19 Vaccine Administration With SARS-CoV-2 Anti-Spike IgG Antibody Levels: An Exploratory Observational Study. J Biol Rhythms. 2023 Feb;38(1):98-108. doi: 10.1177/07487304221132355. Epub 2022 Nov 11. PMID: 36367167; PMCID: PMC9659693.

10. Du PY, Gandhi A, Bawa M, Gromala J. The ageing immune system as a potential target of senolytics. Oxf Open Immunol. 2023 May 3;4(1):iqad004. doi: 10.1093/oxfimm/iqad004. PMID: 37255929; PMCID: PMC10191675.