The durability of vaccine-induced protection: an overview

ABSTRACT

Introduction

Current vaccines vary widely in both their efficacy against infection and disease, and the durability of the efficacy. Some vaccines provide practically lifelong protection with a single dose, while others provide only limited protection following annual boosters. What variables make vaccine-induced immune responses last? Can breakthroughs in these factors and technologies help us produce vaccines with better protection and fewer doses? The durability of vaccine-induced protection is now a hot area in vaccinology research, especially after COVID-19 vaccines lost their luster. It has fueled discussion on the eventual utility of existing vaccines to society and bolstered the anti-vaxxer camp. To sustain public trust in vaccines, lasting vaccines must be developed.

Areas covered

This review summarizes licensed vaccines’ protection. It analyses immunological principles and vaccine and vaccinee parameters that determine longevity of antibodies. The review concludes with challenges and the way forward to improve vaccine durability.

Expert opinion

Despite enormous advances, we still lack essential markers and reliable correlates of lasting protection. Most research has focused on humoral immune responses, but we must also focus on innate, mucosal, and cellular responses – their assessment, correlates, determinants, and novel adjuvants. Suitable vaccine designs and platforms for durable immunity must be found.

KEYWORDS:

• Durability
• immunity
• immune responses
• persistence of immunity
• vaccines
• vaccinology

1. Introduction

‘Waning of immunity’ became a buzzword not only in academia and industry but also among the lay public when it became clear that the protection conferred by COVID-19 vaccines is not as durable as offered by other vaccines like measles. The excitement over the speedy development and rapid deployment of COVID-19 vaccines gradually waned off, and soon, a debate surrounding the durability of immune protection ensued. Thus, the durability of vaccine-induced protection is a hot area of research today. What factors determine the durability of vaccine-induced immune protection? Does the nature of the pathogen (fast mutating virus vs. ‘stable’ virus), the biology of the vaccine (live attenuated vs. inactivated viral vaccine, the addition of an adjuvant and the type), or the vaccination schedule (dose, number of doses and interval between doses) have any bearing on the long term persistence of vaccine-derived immunity? It is also known that natural infections caused by most human coronaviruses, including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV2) and influenza, fail to provide long-lasting protection, unlike other respiratory pathogens like measles, rubella, varicella, and mumps [1]. The current generation of vaccines against all these pathogens also follows a similar pattern.

This review provides an overview of the durability of protection offered by the currently used licensed vaccines. It summarizes the current knowledge, recent advances, knowledge gaps, challenges, and bottlenecks regarding the long-term protection induced by vaccines and how to overcome these.

2. Overview of the durability of protection conferred by the key licensed vaccines

To perform an analysis of the durability of immune protection accorded by the currently licensed vaccines, we have broadly classified them under three heads (Table 1):

1. Vaccines that provide long duration of protection (>20 years).

2. Vaccines that provide moderate duration of protection (5-20 years).

3. Vaccines that provide short duration of protection (<5 years).

Table 1. A summary of currently licensed vaccines grouped based on their duration of protection, along with other vital parameters.

Number	Vaccine	Vaccine type	Correlate of protection (CoP)	Efficacy (point estimate)	Estimated duration of protection		Comments
					Clinical entity	Duration of protection
Vaccines that provide long duration of protection (>20 years).
1.	Measles vaccine	Live attenuated parenteral vaccine	≥120 miU/ml	83% (95% CI: 76–88)	Measles infection and disease	Lifelong protection after seroconversion	Boosting of primary immune response is seen with exposure to wild virus or after re-vaccination
2.	Rubella	Live attenuated parenteral vaccine	Abs ≥10-15IU/ml	80.7%, (95% CI: 73.7–85.8%)	Rubella infection	Lifelong protection	Rubella virus-specific humoral immune responses wane with time after vaccination, but they do so at a moderate rate.
3.	Yellow Fever Vaccine	Live attenuated vaccine (17D strain)	log10 neutralization index (LNI) of ≥0.7	~99%	Yellow fever disease	Lifelong protection	Some waning after 10 years. Boosters were recommended after 10 years till recently.
4.	Hepatitis-B	Inactivated, sub-unit	≥10 mIU/mL	Against infection: 89% Against chronic carriage: 96%	Hepatitis-B disease	Up to 30 years	After 3 doses
5.	Hepatitis-A-inactivated	Inactivated vaccine	ELISA Ab 20mlU/ml	>98%	Hepatitis A infection	At least 25 years	Mathematical modeling suggests that detectable antibodies are estimated to persist for as long as 60 years for the 2-dose schedules.
II. Vaccines that provide moderate duration of protection (5–20 years).
1.	Oral Polio Vaccine	Live attenuated, oral	≥1/8 dilution of NAbs	72% (95%CI: 57–82)	Paralytic polio	Up to 18 years	Data limited from the tropical countries
2.	Inactivated Polio vaccine	Inactivated	≥1/8 dilution of NAbs	89% (95% CI 62%, 97%) with two doses:	Paralytic polio	At least 18 years	Limited studies from the developing and tropical countries
3.	Hepatitis-A-live attenuated	Live attenuated vaccine (H2 strain)	ELISA Ab 20mlU/ml	100%	Hepatitis A infection	At least 15–17 years	After a single dose of H2 strain based live attenuated vaccine in endemic region. Protection may persist longer. Trials on longevity of immunity are still ongoing.
4.	Human papillomavirus (HPV) vaccine	Inactivated, Virus-like particle (VLP) based	ND	For HPV naive at enrollment: 91–100% (64.6% to 86%; 94.2% to 100)	HPV vaccine-induced seropositivity	11–14 years (following full course)	Longitudinal trials are still ongoing. The longest period of preventive effect for the bivalent, 4-valent, and 9-valent vaccine were 11 years in the Costa Rica trial, 14 years in the FUTURE II, and 8 years in the LTFU extension study and the Scandinavian study, respectively.
5.	BCG	Live attenuated, ID	ND (IFNγ-production by CD4 T cells)	37% for all forms of tuberculosis (TB) in children below 5 years of age 42% against pulmonary disease in children below 3 years of age	Pulmonary & extrapulmonary TB	10–15 years	Protection may last longer, may be up to 50–60 years though waning of efficacy does occur.
6.	Diphtheria	Toxoid	0.01–0.1 IU/ml	95.5% (95% CI 92%, 97.4%	Diphtheria disease	11 years	After primary series and two booster doses
7.	Tetanus	Toxoid	0.1 IU/ml	Virtually 100%	Tetanus disease	10 years	After three primary doses and two boosters
8.	Varicella zoster vaccine	Live attenuated parenteral vaccine	GP ELISA ≥5 U/ml	98%	All chickenpox disease	Around 10 years (after single dose)	Several studies have shown that vaccinated people had varicella antibodies for at least 10 to 20 years after vaccination. But these studies were done before the vaccine was widely used and when infection with wild-type varicella was still very common.
9.	Mumps	Live attenuated parenteral vaccine	ND	75.8% (35.6%, 90.9%) with Urabe strain and 64.7% (10.6%, 86.0%) for Jeryl-Lynn strain	Mumps disease	6–7 years	It is estimated that 85% protection is there 6–7 years after 2 doses of the vaccine and decrease to pre-vaccination level by 12 years in the absence of natural boosting
10.	Pneumococcal conjugate Vaccine	Inactivated, polysaccharide conjugate, subunit vaccine	0.20–0.35 mcg/ml (ELISA for Abs)	80% (95% CI58–90)	Pneumococcal disease	More than 6 years	Exact duration of protection is not known; marked variation in the protection rates of different serotypes
11.	Rabies	Inactivated, (Cell culture & embryonated egg-based rabies vaccines (CCEEVs)	NAbs: ≥0.5 IU	Virtually 100%	Rabies infection	9 years	Vaccine induced memory B cells appear to persist for life. Effective recall of the immune response to additional doses, such as for Post-exposure prophylaxis (PEP), are documented for decades after priming.
12.	Herpes Zoster (recombinant) vaccine	Recombinant subunit (glycoprotein E) vaccine with AS01 adjuvant system	ND	97.2% (95% CI, 93.7–99.0; p<0.001)	Herpes Zoster Herpes Zoster ophthamicus Post herpetic neuralgia	10 years	Unlike the live attenuated vaccine, the high efficacy found even after 10 years of primary vaccination.
13.	Pertussis-Whole cell vaccines	Inactivated, whole cell	ND	94% (95%CI: 88–97%)	Pertussis infection	4–12 years	After primary series and childhood boosters
14.	Pneumococcal polysaccharide vaccine (PPSV)	Inactivated, polysaccharide subunit vaccine	ND	74% (95% CI: 54–85)	Pneumococcal diseases	5–8 years	The VE in older adults diminishes in the years following vaccination and is likely absent after some interval, which may be on the order of 5 or more years.
15.	H. influenzae type ‘b’ conjugate vaccine	Inactivated, polysaccharide conjugate, subunit vaccine	0.15 mcg/ml	95–100% (95%CI: 55–100)	H. influenzae disease	Up to 6 years after a booster in 2^nd year	Although vaccine effectiveness declined significantly after the first year of life (p<.001), it remained high until the sixth year of life
III. Vaccines that provide short duration of protection (<5 years)
1.	Meningococcal vaccine	Quadrivalent Subunit vaccine: Bacterial capsular oligosaccharides conjugated to a carrier protein	Serum bactericidal titer of ≥1:8 using baby rabbit complement (rSBA)	79% (49% to 91%) at <1 year post single dose	Meningococcal Meningitis, meningococcal fulminant septicemia	~5 years	Waning of Vaccine efficacy varies with serotype and vaccinees’ age: faster waning in children < 7 years than at older age
2.	Pertussis-acellular vaccines	Inactivated, sub-unit vaccine	ND	84% (95%CI: 81–87%)	Pertussis infection & disease	4–7 years	Evidence of waning of immunity beyond 4 years and little-to-no protection beyond 7 years from last vaccination Primary series, followed by two boosters
3.	Dengue vaccine (CYD-TDV)	Live attenuated viral vaccine (CYD-TDV-Dengvaxia®)	ND (NAbs, variable)	62.0% (95% CI, 56.6–66.7) at 1 year	Virologically confirmed dengue	5 years in seropositive	Waning of protection Efficacy varies by sero-status and severity of disease
4.	Dengue vaccine (TAK-003)	Live attenuated tetravalent dengue vaccine (TAK-003, Qdenga™)	ND (NAbs, variable)	82.2% (95% CI: 87.6–74.5%) at one year	Virologically confirmed dengue	4.5 years	Waning of protection Efficacy varies by sero-status and severity of disease
5.	Cholera vaccine, bivalent	Whole cell killed vaccine	ND (Vibriocidal Abs)	67%	Cholera	5 years	The combined VE after 5 years was estimated to be 65%
6.	Cholera vaccine, monovalnt	Whole cell killed vaccine with recombinant B subunit of cholera toxin	ND (Vibriocidal Abs)	85%	Cholera	6 month to 5 years	The protection lasts only 6 months for children and 2 years in adults.
7.	Japanese encephalitis vaccine-live	Live attenuated SA 14-14-2 vaccine	NAbs: 1:10 (PRNT)	98.5% (CI 90.1–99.2%)	JE disease	5 years (after a single dose)	Recent studies from India find showed a decreasing trend of anti-JEV specific IgG antibody titers following two doses of SA-14-14-2 vaccine. Marked waning in titers noted after even 2 years of vaccination
8.	Japanese encephalitis vaccine-Inactivated	Inactivated (IXIARO®/JESPECT®/JEEV®)	NAbs: 1:10 (PRNT)	91% (95% CI: 70–97)	JE disease	5 years (after 2 primary doses)	−2 dose primary series in adults from non-endemic regions –Modeling suggests protection may last up to 14 years after booster at 15 mo
9.	Typhoid conjugate vaccine	Inactivated, polysaccharide conjugate, subunit vaccine	ND	81.6%; (95% CI: 58.8 to 91.8)	Typhoid fever	Around 5–7 years	Definite waning in anti-Vi IgG antibodies seen after 5 years. To extend protection, administering a booster dose to children ∼5 years after their primary dose may be considered
10.	Typhoid unconjugated Vi-polysaccharide (ViPS)	Typhoid polysaccharide vaccines	ND	69% (95% CI = 28–87%)	Typhoid fever	3 years	To maintain protection, revaccination is recommended every 3 years.
11.	Herpes zoster Live attenuated Vaccine	Live attenuated	ND (CD+ T cells Protective)	Varies with age; 51% overall; 69.8% in 50–59 year ag group and 18% in >80 years	Herpes Zoster Herpes Zoster ophthamicus Post herpetic neuralgia	~5 years	Efficacy is higher and wanes less for hospitalization for HZ and post-herpetic neuralgia than for Herpes Zoster and Herpes Zoster ophthalmicus
12.	Rotavirus vaccines	Live attenuated oral vaccine	ND (Secretary IgA)	77% − 90% in developed, industrialized countries 51% in developing countries	Rotavirus diarrhea	1–2 years	Vaccine efficacy is lower and wanes more rapidly in high-mortality settings than in low-mortality settings
13.	Influenza vaccines-Inactivated	Inactivated split & sub-unit vaccines	HI Abs: 1/40=50% protection (1/320 in children)*	59% (95%CI: 41–71%)	Influenza disease	6 months	There is marked variation in the VE of different influenza sub-types. The decline in VE is more pronounced for A H3 than AH1 viruses.
14.	SARS-CoV2 vaccine	mRNA vaccine (mRNA-1273 vaccine)	ND (NAbs seems protective)	94.1% (95%CI: 89.3–96.8%	Covid-19 symptomatic disease	3–6 months	Duration of protection varies according to the severity of the disease, type of circulating variant, highest for the WT and lowest for Omicron and later sub-lineages

ND= Not Determined.

HI=hemagglutination inhibition (HI).

*The immune response to influenza is multifaceted and there are probably multiple correlates of protection.

2.1. Vaccines that provide a long duration of protection (>20 years)

2.1.1. Measles vaccines

A single dose of vaccine offers lifelong protection to nearly all vaccinees. The primary immune response is boosted with exposure to wild viruses or after re-vaccination [2]. Once seroconverted, protective anti-measles antibodies ≥ 120 mIU/mL are detected for a very long period, probably for life, without any significant waning in the antibody titers. A modeling study estimated the half-life of anti-measles antibodies to be more than 3000 years [3].

2.1.5. Rubella vaccine

Rubella vaccine also induces a robust immune response that is presumed to be lifelong [4]. Rubella virus-specific humoral immune responses wane with time after vaccination, but they do so moderately [5]. Though no absolute immune correlate of protection has been established, a cutoff level of anti-rubella IgG antibodies of ≥ 10 IU/mL is generally protective against rubella disease [4]. One longitudinal study estimated that rubella-specific immunity was maintained, with an estimated half-life of 114 years and no significant rate of titer decrease [3].

2.1.3. Yellow fever vaccine

The live-attenuated yellow fever vaccine has excellent long-term effectiveness. The titer of neutralizing antibodies is the correlate of protection. Plaque reduction neutralization test (PRNT50) assays with a titer of 1 in 10 are used in most clinical trials to correlate protection.

According to Poland et al. [6], 80.6% of World War II soldiers had neutralizing antibodies that lasted longer than thirty years. Neutralizing antibodies have also shown long-term persistence in several additional studies conducted in both endemic and non-endemic countries [7–10]. Since there are no documented cases of Yellow Fever infection in individuals with documented seroconversion, it has been argued that the hypothesis that the vaccine provides lifelong protection is correct [11].

2.1.4. Hepatitis-B vaccine

The Hepatitis B vaccine is a T-cell-dependent subunit vaccine, and hepatitis B infection has a long incubation period, allowing enough time for an anamnestic response to occur if there is contact with the virus. Hence, once seroconversion occurs, the vaccine can provide long-term protection even if antibody titers fall below the protective level of 10mIU/mL.

2.1.5. Hepatitis-A inactivated vaccine

Many modeling and anti-HAV kinetic studies have confirmed that a high level of seroprotection can be achieved for at least 30 years by a single or two-dose vaccine schedule [12,13]. Furthermore, protection against the clinical disease may persist even without detectable antibodies in the presence of memory B and T cells [14].

2. Vaccines that provide moderate duration of protection (5–20 years)

2.2.1. Oral polio vaccine (OPV)

After seroconversion, OPV offers almost lifelong protection against paralytic poliomyelitis, even if the antibody titers fall below detectable levels later in life. However, seroconversion and efficacy vary between different geographical settings: higher in temperate climates in industrialized countries than in developing countries with tropical conditions. According to an Italian study, immune protection against paralytic disease persisted up to 18 years after administration of the last OPV dose, with protective antibodies against poliovirus type 1 and 2 detected in more than 95% of the subjects even after 30 years of the last OPV dose [15].

2.2.2. Inactivated poliovirus vaccine (IPV)

Studies from industrialized countries have indicated that IPV-induced antibodies protect from paralytic polio for many decades, probably for life [16]. According to a retrospective cohort study from Italy, neutralizing antibodies against all three polio types persisted in more than 90% of study participants 18 years after the last vaccine dose [17]. In this study, the IPV induced higher titers of neutralizing antibodies than OPV.

2.2.3. Hepatitis A live attenuated vaccine

Like inactivated vaccines, live attenuated hepatitis-A vaccines also offer a long duration of protection. After a single dose of H2 strain-based live attenuated vaccine in an endemic region, at least 15–17 years of protection has been demonstrated along with the persistence of immune memory [18–20].

2.2.4. Human papilloma virus (HPV) vaccines

These vaccines are unique in that they offer long-lasting protection against HPV-related illnesses even with a single dose, and the protection they offer is virtually sterilizing, meaning that they prevent infection rather than just illness [21]. This is despite them being non-live attenuated vaccines. Bivalent, quadrivalent, and nonavalent vaccines have shown the most extended durations of preventative effect: 11 years in the Costa Rica trial [22], 14 years in the FUTURE II trial [23], and eight years in the long-term follow-up (LTFU) extension study [24] and Scandinavian Study [25]. An Australian real-world effectiveness study [26] has the longest observation time of 12 years for vaccine efficacy (for the quadrivalent vaccine).

2.2.5. Bacille Calmette-Guérin (BCG) vaccine

Even while the BCG vaccine’s efficacy varies greatly depending on the clinical entity and demography, it offers quite a long period of protection – even up to 50 years [27–29]. A thorough analysis found that in certain groups, protection following a baby BCG vaccine could continue up to 15 years; nevertheless, the protective efficacy does eventually wane [30].

2.2.6. Diphtheria

Protective levels of diphtheria antibodies (0.1IU/mL) persist for decades after vaccination, although they wane in a section of vaccinees after ten years [31]. The half-life of diphtheria-specific antibodies is estimated to be around 19 years [32]. Considering this and the fact that diphtheria infection has a short incubation period, and the natural boosting is also limited with high vaccination coverage, its booster is recommended every ten years, especially in industrialized countries, to maintain protective levels. However, recent studies have suggested that the protective titers persist much longer in the majority, and less frequent boosters should be sufficient [33].

2.2.7. Tetanus

The duration of protection accorded by the tetanus vaccine is also similar to the diphtheria antigen. The protective level of 0.1 IU/ml of anti-tetanus antibodies persists for 3–5 years after the primary schedule of 3 doses. Then, it may persist lifelong after boosters in the second and fifth years of life and another during the adolescent age in some people [33]. The half-life of tetanus-specific antibodies is estimated to be around 11 years [31]. However, in most persons, the level approaches minimal protective levels ten years after the last dose [34]. Thus, its booster is recommended every ten years to maintain protective levels. Recent studies have indicated that less frequent boosting might be enough [35].

2.2.8. Varicella zoster vaccine

Many studies from the U.S.A. and Japan demonstrated the long-term persistence of anti-varicella antibodies after a single dose of varicella vaccine [36]. However, there are concerns that these studies were conducted when the virus had a substantial circulation in the community, and there may be some waning now due to the absence of widespread transmission. Later studies have demonstrated a waning in immunity after a single dose of the OKA-strain varicella vaccine [37]. Though anti-varicella antibodies are estimated to have a half-life of 50 years, there are frequent fluctuations in the titers.

2.2.9. Mumps vaccines

Although wild mumps virus infection provides lifelong immunity, recurrences of mumps disease are reported [38]. There are at least 13 different strains of Mumps virus employed in live attenuated vaccines [39]. They differ in efficacy to a certain extent, but overall, they protect 80% of the recipients.

Some studies have reported 60–90% effectiveness after a single dose [39]. According to a Cochrane review of 64 MMR vaccine studies, one dose’s effectiveness was 69%-81% [40].

Another study finds that mumps-specific antibody titers persist for at least 32 months after vaccination and slowly wane off. It is estimated that 85% protection is there 6–7 years after two doses of the vaccine [41] and decreases to pre-vaccination level by 12 years without natural boosting [42]. The antibody titers persist longer with natural boosting: for example, a study from Finland reported 74% seropositivity 20 years after MMR vaccination [43]. A longitudinal study estimated the half-life of anti-mumps antibodies to more than 500 years (95% CI: 90 to infinity) and showed no significant decrease in titers over time [3].

2.2.10. Pneumococcal conjugate vaccines (PCVs)

Though the exact duration of protection has yet to be established, PCVs provide reasonably good protection following a primary infantile schedule [44]. There are few longitudinal studies to measure persistent immunity against pneumococcal diseases. Different experts have observed a marked variation in the protection rate of different serotypes. A study with PCV7 on nasopharyngeal carriage noticed sustained protection for five years [45]. In South Africa, an experimental PCV, PCV9, showed consistent protection for 6.3 years after vaccination against Invasive Pneumococcal Disease (IPD) [46].

2.2.11. Rabies vaccine

Vaccine-induced neutralizing antibody (VNA) after rabies vaccination is considered to be a valuable correlate of protection against rabies, and a titer of ≥ 0.5 IU is taken as a cutoff [47]. Briggs et al. found that 80% of vaccinated subjects still had detectable VNA titer after nine years [47]. Significantly, they did not find any correlation between the VNA titer and the number of vaccine doses received as a part of PrEP or PEP or the time elapsed since the last dose of the vaccine series. However, the intramuscular (IM) schedule induced neutralizing antibodies for a longer duration than the intradermal schedule [48]. A German study of the longevity of vaccination-induced rabies VNA found detectable antibodies in 18 subjects 14 years after their last dose in the Pr-EP and PEP schedules [49]. Furthermore, rabies vaccine induced a robust immune memory that provides excellent ‘immune recall’ even after several years of primary schedule [50].

2.2.12. Herpes zoster recombinant vaccine

This new zoster vaccine is based on glycoprotein E of the varicella-zoster virus (VZV) and has an AS01B adjuvant system. The persistence of humoral immune response [anti-Glycoprotein E (gE) antibodies] and cellular immune response (gE-specific CD4+ T-cells) till six years after two doses of the vaccine has been demonstrated [51]. Boutry et al. followed up with 7413 participants enrolled in the long-term follow-up study of the previous clinical trials to study the durability of vaccine efficacy. They found 84.1% efficacy after eight years of the second dose [52].

2.2.13. Whole cell pertussis (wP)

Various studies have estimated the duration of protection offered by whole-cell pertussis (wP) vaccines, which ranges from 4 to 12 years [53]. Long-term studies have shown a definite waning of protection after wP vaccines and natural infection over this period [53–55]. A study by Campbell et al. from the UK cited 83.7% efficacy in children 10–16 years of age following three primary doses, though a decline in vaccine efficacy was noticed within 1–2 years of the third dose [56]. According to a systematic review, annual loss in the efficacy of wP vaccines ranges from 2–13% [57].

2.2.14. Pneumococcal polysaccharide vaccine (PPSV)

Pneumococcal polysaccharide vaccine is recommended in older adults and children with specific risk factors. On vaccination, the antibody levels decline over time after an initial rise and reach almost baseline levels within 4–7 years of vaccination [58]. Extensive studies in older adults have shown vaccine effectiveness wanes over time, and effectiveness may be absent after five years. However, a large cohort study, mainly in adults over 65, has shown good protection against severe pneumococcal infections even after nine years [59].

2.2.15. Haemophilus influenzae type b (hib) conjugate vaccine

Haemophilus influenzae type b (Hib) conjugate vaccine is highly immunogenic with an estimated efficacy of 95–100% after primary series [60]. Most experts believe that Hib conjugate vaccine provides a long-lasting immunity despite waning in titers [61]. However, no exact duration of protective immunity is known, and the need for a booster dose following the primary schedule is still uncertain [62]. It is generally believed that the Hib conjugate vaccine protects at least for five years after completion of the primary series. Many countries have successfully controlled the Hib disease with a three-dose primary schedule, but some countries had to introduce a booster dose after a few years [62,63]. As per some studies, the protection offered by three doses in infancy lasts only till 2nd year of life and wanes quickly [64,65]. The anamnestic response to booster dose is excellent [64].

2.3. Vaccines that provide short duration of protection (<5 years)

2.3.1. Meningococcal vaccines

Meningococcal polysaccharide vaccines, being T-cell independent vaccines, do not provide durable protection/memory-cell response. In younger children, 2–4 years of age, the protection lasts only a few months, while in older children, it lasts 2–3 years. Revaccination again protects for a similar duration [66,67].

Meningococcal conjugate vaccines offer better protection than polysaccharide vaccines, but even with these, the efficacy wanes over the years. The serological correlate of protection is serum bactericidal titer of ≥ 1:8 using baby rabbit complement (rSBA) [68,69]. Immunogenicity study in children aged 7–9 years has shown that seropositivity rates fall from 97.3% to 63.6% for serogroup A and 87.9% for other serogroups (C, W, and Y135) 2 years after vaccination and that falls to a mere 20% after six years [70]. Cohn et al. have shown that the vaccine efficacy of a single dose falls from 79% (49% to 91%) at <1 year post-vaccination to 61% (25% to 79%) at 3 to <8 years post-vaccination [71]. The waning in the protective antibody titers following meningococcal conjugate vaccines also varies with the child’s age, with waning faster in kids under five years of age than kids above five years of age [70].

2.3.2. Acellular pertussis (aP) vaccines

Compared to wP vaccines, waning is faster with acellular pertussis (aP) vaccines. Schwartz et al. observed that the duration of protection following aP vaccines declined rapidly following four years of vaccination despite high early effectiveness [72]. The efficacy drops from around 90% in the first year after the last dose of the aP vaccine to 30–40% 6–8 years after the last dose [73–76]. Waning of protection after TdaP vaccines is even faster: some studies have shown the protection wanes quickly, with efficacy dropping to as low as 8.9% after four years [77–80].

2.3.3. Dengue vaccines

Currently, two live attenuated dengue vaccines – CYD-TDV (Dengvaxia™ by Sanofi) and ‎TAK-003 (Qdenga™ by Takeda) are licensed and approved for use in different populations in some countries. According to data from three efficacy trials, CYD-TDV offers protection for five years against severe dengue among seropositive individuals [81]. Another live dengue vaccine, TAK-003, has been evaluated for 54 months. The published data showed a 62.0% efficacy against virologically confirmed dengue (VCD) and 83.6% against hospitalized VCD [82]. According to unpublished follow-up data, the vaccine offered 64.2% vaccine efficacy against VCD in seropositive individuals and 53.5% VE in seronegative individuals after 54 months. The vaccine efficacy against hospitalized dengue was more than 80% after 54 months of follow-up [83].

2.3.4. Cholera vaccines

Two types of cholera vaccines are available globally: monovalent and bi-valent-killed whole-cell oral cholera vaccines. While the prototype of the former is WC-rBS (recombinant B subunit of cholera toxin – Dukoral®), there are three different bi-valent vaccine products available globally that contain O1 and O139 strains (without the B subunit) and marketed as Shanchol™, Euvichol™ and mORCVAX™ All of them, barring mORCVAX™ (mainly used in Vietnam), are WHO-Pre-qualified [84].

The estimated duration of protection of these cholera vaccines ranges from 6 months to 5 years. For the monovalent Dukoral™ vaccine, the protection lasts only six months for children and two years for adults. For the bivalent, whole-cell vaccine, Shanchol™, protection lasts up to 5 years after vaccination. In a large RCT conducted in Kolkata, the efficacy differed in different age groups – highest in older children and adults and lowest in young kids. The combined VE after five years was estimated to be 65% [85].

2.3.5. Japanese encephalitis vaccines

Japanese encephalitis vaccine-live (SA-14-14-2): Studies from Nepal show that this live attenuated JE vaccine based on the SA-14-14-2 strain provides reasonably good protection for five years after a single dose. A case-control study in Nepalese children found 96.2% effectiveness after five years of a single dose [86]. Another case-control study among adults finds 77.0% (95% CI: 67.0–83.0) effectiveness after seven years of a single dose administration in two districts of Assam, India [87]. However, a recent cross-sectional study conducted in the Gorakhpur district of India finds that 97.74% of samples were negative for anti-JEV-specific IgG antibodies after two years of the second vaccine dose [88].

Inactivated Vero cell-derived vaccines (IXIARO®/JESPECT® (Valneva, Austria) & JEEV®(BE, India): Data on the long-term protection against the clinical disease from the endemic region is limited. A Philippine study with IXIARO® among 300 children finds that 90% of un-boosted subjects had protective anti-JE antibodies after three years of primary vaccination of two doses [89]. A 5-year follow-up study among two-dose recipients of the IXIARO vaccine in Austria finds that 81% of the subjects retained the protective antibody titers [90]. Another study from the non-endemic region demonstrated the persistence of sero-protection for six years after two primary doses of IXIARO and a booster dose after 15 months [91].

2.3.6. Typhoid vaccines

Vi-polysaccharide vaccine: A T-cell independent antigen, it does not induce memory cells and immunoglobulin class switching. Hence, it does not offer long-term protection and requires revaccination every three years for continued protection [92]. Even within the three years, vaccine efficacy falls from 64% after 21 months to ~ 55% in the third year [93].

Typhoid conjugate vaccines: Conjugate vaccines, being T-cell dependent, induce robust immune response with the production of memory cells, thus offering long-term protection. One study conducted with the vaccine developed with a nontoxic recombinant protein that is antigenically identical to Pseudomonas aeruginosa (Vi-rEPA conjugate vaccine) among two to five-year-old Vietnamese children demonstrated 89% efficacy after 27 weeks of active surveillance followed by 19 weeks of passive surveillance [94]. Studies performed on another conjugate vaccine using tetanus toxoid as a carrier protein, Vi-TT (Typbar-TCV™), demonstrated that protection following a single dose might persist for up to five years [95,96]. A longitudinal study finds the persistence of anti-Vi-IgG antibodies up to 7 years following primary vaccination of children in both boosted and un-boosted cohorts. However, there was a significant waning in the titers after five years, and the manufacturer recommended a booster after five years of the primary dose [96].

2.3.7. Herpes zoster live attenuated vaccine

This live attenuated vaccine gives protection for a shorter duration than the recombinant, inactivated vaccine. Efficacy against Herpes zoster and post-herpetic neuralgia hospitalization is higher and better maintained. A real-world effectiveness study demonstrated that herpes zoster vaccine efficiency decreased from 67% (95% CI: 65% to 69%) in the first year to 15% (5% to 24%) after ten years [97]. Efficacy against post-herpetic neuralgia dropped from 83% (78% to 87%) to 41% (17% to 59%) during the same period. Vaccine efficacy against herpes zoster ophthalmicus decreased from 71% (63% to 76%) to 29% (18% to 39%), while that against herpes zoster hospitalization dropped from 90% (67% to 97%) to 53% (25% to 70%) in five to eight years [97].

2.3.8. Rotavirus vaccines

Vaccine effectiveness of live attenuated rotavirus vaccines declines more rapidly in regions with high burden-high mortality than in industrialized countries having low burden-low morbidity [98]. According to a meta-regression study, the efficacy of live oral rotavirus vaccines waned more rapidly in high-mortality settings, and pooled efficacy after 12 months was only 44%. In contrast, in low and middle mortality settings, the corresponding figure was 77%–94% [99]. Some efficacy studies from the low burden-low low mortality countries have demonstrated sustained protection against severe rotavirus disease even after three years of primary vaccination [100,101].

2.3.9. Influenza vaccines

Vaccines against influenza do not produce long-term protection. After immunization, the anti-HA antibodies peak 2–4 weeks after vaccination in primed individuals, whereas in unprimed individuals and older adults, they peak ≥4 weeks after vaccination. After six months, the titers drop by more than 50%, with the amount of the drop proportional to the highest titers attained. The titers then stay constant for two to three years [102]. According to clinical trial data, immunity against antigenically identical strains to those in the vaccination lasts for roughly 6–8 months [103].

The vaccine effectiveness (VE) of the various influenza subtypes varies significantly. AH3 viruses have a more marked decrease in VE than AH1 viruses. Moreover, the VE is influenced by the interval since immunization. According to a comprehensive review and meta-analysis, VE for influenza virus subtypes A/H3 and type B is significantly less at 3–6 months after vaccination than 0–3 months after vaccination [104].

A different study discovered that the influenza A(H3N2), influenza B, and influenza A(H1N1) pdm09 viruses caused a 7% (absolute) monthly drop in VE. Patients who had received influenza vaccinations in the previous season showed a more marked decline in VE [105]. An Australian study discovered an intra-seasonal drop in influenza vaccine effectiveness. The study found that the best defense against influenza verified in a lab was when immunization was given within two months of the onset of symptoms [106]. Vaccine effectiveness could disappear as soon as 90 days after inoculation, as per a 2018 analysis of 11 recent studies on the vaccine’s durability [107].

2.3.10. SARS-CoV-2 vaccines

There is no known broad estimate of the duration of protection offered by the SARS-CoV-2 vaccines against COVID-19 disease, which varies according not only to the disease state and type but also to the circulating variants. Further, despite the extensive use of different vaccines and hundreds of studies over three years, no reliable immune correlate of protection against the disease could be ascertained so far. Overall, neither the infection nor the vaccines provide lasting protection. The effectiveness of these vaccines rapidly wanes over time after primary and booster vaccination. Most studies, including systematic reviews, found that protection waned significantly within 3–6 months of a vaccine dose, especially against the Omicron variant.

An extensive review evaluated 78 studies on vaccine-specific vaccine efficacy/effectiveness of four COVID-19 vaccines before the advent of the Omicron variant concluded that VE against symptomatic disease waned by 20–30% by six months of the primary series. However, the VE remained high, around 70% against severe disease, and declined only 10% after six months [108].

Another review based on 40 peer-reviewed studies finds that the VE against the omicron variant was only 20% after six months of the primary series and 30% after nine months of a booster dose – a faster waning of VE noted against the Omicron than the Delta variant [109].

Another review based on 41 studies on the performance of exclusively inactivated COVID-19 vaccines found that primary VE had waned significantly after six months [110]. The study noted VE of 52.8% against the Delta variant, which went down sharply against the Omicron (16.4%). However, like mRNA vaccines, the VE against severe disease remained good even after six months of primary series, which improved after a booster dose [110].

3. Immunological basis of long-term protection conferred by vaccines

Vaccines induce immune responses that are highly complex and include orchestrated actions of a wide range of immune cells in both innate and adaptive immune systems (Figure 1). Ultimately, with most current vaccines, protection is provided through pathogen-specific antibodies, which target specific epitopes in pathogens or their toxic components. Antibodies are exclusively produced by a subset of B-lymphocytes (B-cells) called plasma cells. The process of antibody production begins with the vaccine antigens reaching the draining lymph nodes from the injection site, where they are captured by specialized macrophages in the sub-capsular region and then transported to B- -cell zone (follicles) (step ‘a’ in Figure 1). Here, B-cells are activated, and activated B cells migrate toward the border region between B-cell follicles and the T-cell zone (called marginal zone) [111].

Figure 1. Schematic representation of vaccine-induced immune responses in the draining lymph node.

(Adapted from: Chen Z, Gao X, Yu D. Longevity of vaccine protection: Immunological mechanism, assessment methods, and improving strategy. View, 2022; 3, 20200103).

After that, there are two pathways: One, activated B-cells can induce extra-follicular response (without any help from T-cells), which leads to the production of short-lived plasma cells (step ‘b’ in Figure-1). Bacterial antigens like lipopolysaccharides induce this type of response. As the name suggests, these short-lived plasma cells secrete antibodies for a short time; thus, the vaccine-induced protection is only short duration. Without T-cell help, the antibodies produced are of low to modest affinity and mostly IgM type with no isotype switching [111]. Of note, this reaction is relatively rapid, leading to the appearance of IgM antibodies within a few days of vaccination. Vi Polysaccharide typhoid vaccine is a classic example of this [112].

The second pathway is the germinal center (GC) response induction. This pathway involves intricately coordinated activities in different lymph node zones and is relatively slower: it takes roughly two weeks for the germinal centers to develop [113]. In the T-cell zone, the antigen is presented by major histocompatibility complex (MHC) class II of antigen-presenting cells (APC) like dendritic cells (DC) to naïve CD4+ T cells, leading to their functional differentiation to helper T cells (Th cells) (step ‘c’ in Figure-1). These Th cells provide helper signals to activate B-cells in the marginal zone to lead to extra-follicular response, producing short-lived plasma cells (step ‘d’ in Figure 1). These short-lasting plasma cells start dying after some time, resulting in reduced antibody titers noted 4–8 weeks after vaccination [114]. However, because T-cells help in the form of type-1 cytokine interferon-gamma (IFN-γ) (produced by follicular helper T-cells (TFH cells) and Th1 cells) or Type 2 cytokines interleukin-4 (IL-4) [produced by TFH and Th2 cells], there is isotype switching to IgG1/IgG3 or IgG1 and IgE respectively. Some primed CD4+T-cells are committed to differentiation toward TFH cells (step ‘e’ in Figure 1), and they support the initiation and maintenance of GC reaction [114,115].

The GC reaction is initiated by the migration of some activated B cells toward germinal centers on getting signals from primed T-cells and follicular dendritic cells (FDCs) (step ‘f’ in Figure 1). The FDCs are essential here: they attract antigen-specific B and TFH cells and capture/retain antigens for extended periods. B cells attracted by antigen-bearing FDCs become the founders of the GC reaction. Each GC contains B-cells of a single antigen only. These B-cells undergo massive clonal proliferation, somatic hypermutation, and affinity maturation [selection of fittest B-cells (with highest affinity) after several ‘rounds’ of selection].

Moreover, they differentiate into long-lasting plasma cells (step ‘g’ in Figure 1) that secrete large amounts of high-affinity antibodies for extended periods (primary immune response) [115]. Some GC B-cells differentiate into memory B cells (step ‘h’ in Figure 1). Memory cells persist as resting cells until re-exposed to the same antigen when they re-proliferate and differentiate into plasma cells, secreting large amounts of high-affinity antibodies (secondary immune response) [115].

The decline of antibody titers after this secondary immune response is much slower than that of the primary immune response. Thus, a rapid increase in antibody titer is noted within days of infection with the same pathogen later or after a booster dose of the vaccine. During the GC reaction, a fraction of plasma cells can migrate toward long-term survival niches mainly located within the bone marrow, where their survival and antibody production may persist for years [116]. The long persistence of antibodies can be predicted by measuring antibody titers between 6–12 months of vaccination, as by this time, all short-term plasma cells have disappeared, and in the absence of repeat vaccination, the antibodies in serum are those secreted by long-lasting plasma cells only [117].

In addition to this antibody-mediated immune response (humoral immune response), CD8+ T cell-mediated cytolysis is a crucial mechanism of cellular immunity against intracellular infections. It is induced in the T-cell zone where naïve CD8+ T-cells are activated by cross-presentation of the antigen via the MHC class I molecules on dendritic cells that drive their differentiation into short-lived effector CD8+ T-cells (step ‘i’ in Figure 1) or resident memory CD8+ T-cells (step ‘j’ in Figure 1) [118]. Like a humoral immune response, most short-lived cytotoxic effector cells enter programmed cell death at the end of primary immune responses. In contrast, memory CD8+ T cells persist over a more extended period, and they can rapidly proliferate into a massive wave of effector cells upon re-exposure to the same pathogen. In addition to protecting intracellular antigens, the memory function of CD8+ T cells has been suggested to be a significant protection mechanism for the elderly with inadequate antibody responses [114].

Moreover, a new subset of CD8+ T cells that persist in non-lymphoid tissues for an extended period and can control reinfection has been recently identified. Termed tissue-resident memory T cells (TRM) they are of great interest for developing vaccines against infections entering through respiratory and digestive tracts where conventional antibody-based vaccinations cannot induce sufficient capacity to neutralize pathogens during initial infections [119].

The critical determinants of the persistence of humoral immunity are two broad immune mechanisms – memory B-cell dependent and memory B-cell independent. The immunity in the latter is provided through antibodies produced by the long-lived plasma cells residing in the bone marrow niches [120]. The memory B-cells themselves do not provide protection, but they divide and differentiate into plasma cells after antigenic exposure to secrete large amounts of antigen-specific antibodies [3]. So, to assess the longevity of immunity induced by an immunogen, measuring the memory B-cell counts should provide an estimate of the durability of immunity. However, studies have shown that this correlation does not exist for all vaccines in real life. While in the case of specific antigens like measles and rubella, the memory B-cell population remains stable and correlates well with antibody levels decades later, whereas, in the case of some other antigens like varicella – zoster virus, Epstein – Barr virus, tetanus, or diphtheria, no such correlation exists [3]. It is also noticed that this association fails to exist for those vaccines requiring multiple or repeated doses. This observation reflects that the mere persistence of memory B-cells may not guarantee the durability of antibodies, and some other mechanism may be involved in maintaining the long-term antibody levels. One such mechanism could be ‘imprinted lifespan’ phenomenon in which B-cell signaling during the induction of antigen-specific immune response determines the life span of the plasma cells [121]. Most antigens induce memory B-cell formation, but the duration of antibody production is not the same. This hypothesis may explain why certain antigens provide long-term immunity while others provide only short-term protection.

During the process, the exact mechanisms responsible for differentiating immune cells toward different subsets and pathways are also poorly understood even today. However, the induction of good GC reactions, many long-lasting plasma cells, and the formation of memory B-cells and T-cells are essential for durable, long-lasting vaccine-induced protection [115] (Figure 2).

Figure 2. Key immunological determinants of durable vaccine-induced immune responses.

Both B-cell and T-cell responses help in providing durability to vaccine-induced immune responses. A. Germinal centers (encircled) in lymph nodes are factories of B-cell production and their maturation. B. Memory B cells in lymphoid tissues like the spleen. C. Long-lived plasma cells move to the bone marrow niches and survive there, providing long-lasting immunity.

D. Memory T-cells in the lamina propria and epithelium of the intestine. E. Tissue-resident memory T-cells (TRM) in the nasal passages and lungs. These cells are in non-lymphoid tissues, such as skin, gut, and lung airways, and do not recirculate through the blood. Most T cells mature in the thymus gland before subsequent export to the periphery.

4. Determinants of the longevity of antibody response

Certain known factors determine how long the vaccine-induced antibody responses can be expected to last (Table 2):

Table 2. Factors determining durability of protective immunity.

Parameters	Long durability	Short durability
Antigen/Vaccine related factors
Antigen form	Particulate antigens (virus particles or aggregated proteins)	Homologous monomeric/soluble antigens
Antigen type	T-cell dependent (Protein)	T-cell independent (polysaccharide)
Antigen valence	High	Low
Adjuvant/s presence & type	Addition of depot or slow-release formulations	Non-adjuvanted inactivated vaccines
Antigenic diversity	Low	High
Vaccine platform	Live attenuated (replicating antigen), Virus like particle (VLP)	All other platforms (Non-replicating antigens)
Antigen dose	Higher	Lower
Vaccination schedule	At least 4–8 weeks between priming doses and 6 months interval between primary doses and booster	Schedules with shorter interval
Route of administration	Intradermal/subcutaneous administration and heterologous prime-boost routes may facilitate longevity of immunity	Homologous, conventional routes of administration
Vaccinee related factors
Age at vaccination	Older children and adults	Extremes of age
Gender	Female gender	Male gender
Genetic factors	HLA Class II Polymorphism and individual HLA genotype may affect immunity	HLA Class II Polymorphism may have a negative impact on immunity
Gut microbiome	Individual’s baseline gut microbiome composition and gut metabolome may positively impact immunity	Individual’s baseline gut microbiome composition and gut metabolome may have negative impact on immunity
Target pathogen and disease related factors
Incubation period	Long	Short
Force of infection	Lower	High
Site of infection	Systemic infection	Mucosal infection
Clinical endpoint	Protection against severe disease	Protection against infection

4.1. Vaccine- and vaccination-related factors

4.1.1. Vaccine platform

The vaccine platform is crucial to determining longevity. Among all vaccination platforms, only live-attenuated and virus-like particle (VLP)-based vaccines elicit long-lasting antibody responses that can endure for several decades, or even a lifetime, without the need for further exposure to the antigen or reactivation of immunological memory. Amanna et al. conducted a long-term study on the levels of specific antibodies against viral antigens (vaccinia, measles, mumps, rubella, varicella-zoster virus, and Epstein-Barr virus) and non-replicating antigens (tetanus and diphtheria) in 45 individuals over up to 26 years. They discovered that the antibody responses against the viruses remained remarkably stable, with estimated half-lives ranging from 50 years for the varicella-zoster virus to over 200 years for other viruses like measles and mumps [3]. The antibody responses to non-replicating antigens (tetanus and diphtheria) declined faster, with estimated half-lives of 11 years and 19 years, respectively [3,121]. Live vaccinations, in contrast to non-live antigens, cause activation of several lymph nodes due to the multiplication and spread of microbes [117]. The process of microbial replication leads to a constant production of antigens, which in turn contributes to an intense and persistent immune response. VLP-based vaccines, such as the Human Papilloma Virus (HPV) vaccine, consist of supramolecular nanoparticles with highly repetitive antigen sequences displayed on their surfaces. The high antigen valency of VLPs, which refers to how densely the vaccine antigen is presented to the immune system, can significantly enhance early B-cell activation and the persistence of GC responses. This, in turn, leads to increased, long-lasting plasma cell differentiation and thus results in a durable and long-standing immune response [122].

COVID-19 vaccines are attractive, as multiple vaccines have been developed, primarily based on its spike antigen, but on different platforms [123]. For example, Moderna’s mRNA vaccine induces high titers of vaccine-induced binding and neutralizing antibodies and CD4 and CD8 cells. However, these wane off by six months, while Janssen’s vaccine, which is a virus vector (Adenovirus-26) based vaccine, induces antibody titers, CD4 and CD8 cells that have lower peak than mRNA vaccine, but persist longer (up to 8 months) [124]. Further, studies have shown that boosting with a vaccine from a different platform (heterologous boosting) induces a better immune response than a homologous schedule [125].

4.1.2. Antigen form

The form of the antigen influences the immune response. Particulate antigens, such as virus particles or aggregated proteins, stimulate more effective antigen uptake and migration by dendritic cells. They lead to more robust responses from CD4+ and CD8+ T cells than when the antigen is monomeric or soluble [126]. Therefore, particle antigens and heat- or chemical-induced aggregated antigens elicit a more robust and long-lasting immune response than soluble, monomeric antigens. Nevertheless, several practical instances deviate from this principle. For instance, the recently approved RTS, S vaccine for malaria consists of a repeating, particulate antigen combined with a potent adjuvant [127]. Nevertheless, this vaccine induces a protective immune response only in around 36% of individuals at vaccination, and the level of protection diminishes to 0% over three years [128].

Another recent development in vaccinology is the ‘structure-based’ design of protein antigens (now termed ‘designer antigens’), which delineate the antigenic structures in the ‘pre-fusion’ and ‘post-fusion’ forms. The advent of new imaging techniques like X-ray crystallography and cryogenic electron microscopy (Cryo-EM) has made it possible to study these forms. Antibodies directed against the ‘post-fusion’ (after the antigen fuses with the host cell) shape do not thoroughly neutralize the circulating form of the virus before it binds to cells, known as the ‘prefusion’ form. Antibodies directed against the epitopes, exposed during only the pre-fusion form, are highly potent in neutralizing the virus. The knowledge about this concept led to the successful development of respiratory syncytial virus (RSV) vaccines and has also been employed in designing a few mRNA and protein-based COVID-19 vaccines [129].

1. Antigen type is a crucial determinant of the longevity of immune responses elicited by a vaccine. Polysaccharide antigens are ‘T-cell independent’ and do not induce TFH cells and GC reaction in the absence of T-cell help (vide supra) [117]. Thus, the antibody response to these antigens is predominantly IgM type, low titers of low-affinity IgG, and only of short-duration [117]. Hence, the antibody response’s durability and ‘quality’ are suboptimal. Conjugation of polysaccharide antigen to a ‘carrier’ protein can lead to induction of TFH cells, GC reaction, and thus high-affinity antibody response with isotype switching and immune memory, leading to longer-term protection, as seen with Pneumococcal conjugate and typhoid conjugate vaccines [130].

2. Adjuvants. Adjuvants improve the immune response to inactivated vaccines in many ways, such as modifying how the antigen is delivered, how long it persists (using depot or slow-release formulations), and boosting Th responses (immunomodulation) [131]. Adjuvants can enhance the durability of vaccine-induced immunity by enhancing both the quality and intensity of immunological responses.

3. Antigen dose is also a factor as far as the durability of vaccine-induced immunity is concerned. An increase in antigen dose, in general, enhances immune response by increasing the availability of the antigen for B/T-cell binding. However, there is some complexity as the antigen dose is also shown to impact the induction of T-regulatory cells (Tregs) apart from affecting Th1/Th2 bias and recruitment of Th17 and TFH cells [132].

4. The vaccination schedule also regulates the magnitude and duration of the antibody response. When priming doses are administered at intervals of less than one month, the resulting immune responses are less long-lasting than when the same number of vaccine doses are given at longer intervals (1-2 months). This is because fewer post-GC B cells are generated, which are capable of long-term survival. A shorter period between waves of primary reactions increases competition, negatively impacting durability. For the best memory retrieval and enhanced immune responses, it is necessary to have longer intervals of at least 3 to 4 months. The optimal timing for a booster dosage is at least 4-6 months after the last priming dose, allowing for the necessary affinity maturation of B-cells in the germinal center and creating memory cells [117]. Administering the booster dose ‘prematurely’ leads to elevated antibodies at the boosting time, creating antigen-antibody complexes, which diminishes the antigens available for B-cell priming. Additionally, antibody-mediated feedback mechanisms may directly affect B cells negatively. The optimal schedule for non-live T-cell dependent immunizations that operate on the ‘prime-boost principle’ is ‘0, 1, 6 months’ [117].

5. Route of administration. The immunological response to a vaccine can differ depending on the route of administration. For instance, Styles et al. showed in their animal study that intradermal vaccination led to better antigen retention in the lymph nodes than intramuscular administration, which resulted in a more robust and longer-lasting activation of antigen-specific GC T and B cells [133]. Jegaskanda et al. showed that intranasal live-attenuated influenza vaccine, followed by a booster of intramuscular subunit vaccine, resulted in a robust immune response [134]. Similarly, administering intramuscular mRNA-lipid nanoparticles as the initial dose, followed by intranasal protein vaccine as a booster, led to a strong and effective immune response against SARS-CoV2 [124]. Hence, a combination of various platforms and delivery methods can enhance the durability of protection.

4.2. Vaccinee-related factors

Age at vaccination: The vaccinee’s age at the time of vaccination also affects vaccine antibody persistence, as the response is shorter at both extremes of age because of immaturity and senescence of the immune system, respectively [117]. In infancy, the immune response to live attenuated vaccines is also adversely affected by preexisting antibodies transferred antenatally through the placenta [135]. Even immune response to non-live vaccines is affected by these maternally-derived antibodies but to a lesser extent.

Gender: Although this aspect is not yet well studied, some indications indicate that immune response might also vary with gender. Studies have demonstrated that females elicit more exuberant immune responses to infections than males [136,137].

Genetic factors: Antigen epitopes associated with many MHC molecules are more likely to induce response. Gene polymorphisms in critical molecules required for B and T cell activation/differentiation molecules affect the quality of antibody responses. Individual and community variations of MHC molecules [human leukocyte antigen A2 (HLA A2)] affect T-cell responses significantly [138].

Disease conditions: Certain disease conditions also affect vaccine antibody persistence. Increased catabolism (as in HIV) or urinary or digestive tract antibody loss reduces vaccination antibody persistence. Immunosuppressive medicines and conditions impact the durability of vaccine-induced protection. Recent studies suggest obesity may accelerate the waning of COVID-19 and influenza vaccine efficacy [139].

Gut microbiome : Recent research reveals that the gut microbiome impacts the development of the immune system and immunological response to vaccines. The way by which the establishment of gut microbiome at/after birth affects childhood vaccination response is unknown [140,141].

4.3. Target-pathogen related factors

The target pathogen and its pathogenicity significantly influence the immune response and longevity. For instance, the incubation period and the force of infection transmission (the pace at which illness is acquired in a community) impact the effectiveness of vaccines. A lengthier incubation period allows for a more efficient memory response and enhanced long-term protection against symptomatic illness [124]. This phenomenon has been extensively documented during the SARS-CoV-2 pandemic, wherein the level of protection against infection declined as the incubation periods of new strains of SARS-CoV-2 reduced [142]. Moreover, it has been found that the effectiveness of vaccines is generally greater in regions where viral transmission, or the force of infection, is lower. This phenomenon was demonstrated in the case of a pentavalent rotavirus vaccine, which showed real-world efficiency ranging from 45% to 90% [143]. OPV also exhibited significant variations in effectiveness [144].

Licensed and experimental vaccines against viruses that replicate on mucosal surfaces without causing systemic infection/significant viremia also fail to induce durable protection. Natural infection with these viruses [like influenza, parainfluenza, RSV, SARS-CoV2, and other ‘human common cold viruses’] also does not provide long-term protection. The possible factors include: (a) They do not come in contact with multiple immune compartments and immune-competent cells, unlike other viruses like measles, mumps, rubella, smallpox, etc., (b) they have a shorter incubation period, as they start causing illness just after mucosal replication (the time required for systemic spread after mucosal replication is cut-off) [1]. Due to the shorter incubation period, the immune system does not get adequate time to mount an adequate/robust immune response; (c) the half-life of nasal secretary IgA is much shorter than serum IgG. Thus, the viruses that induce mainly mucosal immune responses do not result in durable protection against these viruses [145,146]. There is another explanation from an evolutionary point of view: Unlike other immune compartments, mucosal surfaces regularly come in contact with a much larger number of antigens. Hence, they have evolved to ‘tolerate’ less dangerous antigens and down-regulate immune responses to them to minimize bystander tissue damage, focussing on more dangerous antigens for robust immune response. The mechanisms for this immune ‘decision-making’ have not been fully understood yet [1]. Viral genetic variability (number and variety of viral strains/variants that are circulating) also affects vaccine efficacy adversely, as is readily observed with influenza and SARS-CoV2 viruses [147,148].

4.4. Other factors

Some other ‘environmental factors,’ largely unknown, might also affect vaccine-induced immune response. For example, there is a drastic difference in immune response to oral polio vaccine (OPV) among tropical and temperate countries [144]. One hypothesis that explains this effect is that in tropical countries, multiple enteric pathogens are in circulation that affect the ‘uptake’ of the vaccine by the immune system [149].

Even the time of day a vaccine is delivered has been shown to affect immune response robustness. The effect of the circadian clock on critical immune cell functions, including cytokine production, cell trafficking, dendritic cell activity, and T and B cell activity, has been shown; however, the exact mechanism of its effect on the immune response at the cellular or molecular level is still unclear [150,151].

5. How can we improve the durability of vaccine-induced protection?

5.1. Challenges and the way ahead

Despite the vaccines’ 225-year success in controlling infectious disease, improving quality of life, increasing life expectancy, and generating substantial economic benefits, it is ironic that we are still learning how the best vaccines work and how to improve vaccine design to improve protective efficacy. Most of the current vaccines have been empirically developed. Vaccine durability assessment is also a ‘wait-and-see’ method due to ignorance of immunological memory mechanisms and challenges in measuring cellular components that induce long-lasting immune protection [152]. Recent advancements are beginning to reduce our knowledge gaps in underlying mechanisms of vaccine-mediated protection and long-term immunity. We may induce more effective and long-lasting immunity with fewer dosages by exploiting these nuances and optimizing immune response linkages.

Natural infection-induced immunity is usually more persistent than vaccine-induced protection. Exploring this disparity is one approach to developing more durable protection vaccines. Beukema et al. [153] prolonged antigen delivery to replicate natural infection antigen dynamics to improve influenza vaccination durability in mice. They compared the immune response to standard prime-boost immunization with a 28-day interval to that of daily doses of whole-inactivated influenza virus vaccine for 14, 21, or 28 days. The 28 days of extended antigen administration achieved the highest cellular and humoral immune response levels, followed by 21 and 14 days of delivery and prime-boost immunization [153]. Prolonging vaccine delivery also improved the quality of antibody response, as shown by significantly high levels of high avidity, balanced IgG subclass, and cross-reactive antibodies. Lee et al. found that long-prime, slow-delivery (12 days) priming of HIV envelope protein immunogen in rhesus monkeys led to more memory B-cells, higher antibody somatic hypermutation, and more robust immune responses to non-immunodominant epitopes [154]. Further research is needed to identify the optimal antigen delivery methods and formulations that prolong antigen availability, elicit long-lasting and protective immunity against influenza and other viruses, and vaccines that provide long-term protection with fewer doses. Phase 1 of the HIV vaccine clinical trial on this concept is underway (NCT05471076) [124].

Unlike unadjuvanted platforms or those with a single adjuvant, replicating viral vectors mimic natural infections and activate several receptors and inflammatory pathways to sustain immune responses. Therefore, early innate signals differ by pathogen or platform and may be surrogate endpoints to accelerate vaccine development and enable more durable protection [124]. Immune correlates of protection by most modern vaccines are antibodies against pathogen antigens [155]. Since the cellular response is difficult to measure, we have mainly focused on humoral antigen response. However, the quantitative analysis and functional characterization of CD4+ and CD8+ T-cell memory have advanced in the recent 2–3 decades. Multiple methods, such as MHC Class I tetramers, peptide-induced intracellular cytokine labeling, and IFNγ ELISPOT, can evaluate the frequency of antigen-specific T-cell responses [156]. With advanced flow cytometry equipment and reagents, many T-cell functions and phenotypic markers can be evaluated simultaneously. These investigations and advanced microarray analysis of T-cell gene expression profiles have provided information on memory T-cell response [126]. For instance, antiviral T-cell memory lasts decades after smallpox immunization [157,158] and SARS-CoV-1 infection [159]. Despite all the information and the growing consensus that for the most challenging infectious diseases (e.g. AIDS, malaria, and tuberculosis), a combination of effective pathogen-specific humoral and cell-mediated immunity may be needed to create an effective vaccine, we are still far from harnessing cellular immunity. Identification and validation of T cell-specific correlates of immunity (or co-correlates of immunity of T cells and antibodies needed for vaccine-mediated protection) will go a long way in achieving tremendous success in this field.

New adjuvants should also be explored to prolong vaccine-induced protection. Inactivated and recombinant vaccines use adjuvants to boost vaccine-mediated immune responses, increasing seroconversion rates, antigen dose sparing, and fewer doses for similar protection. Alum salts, the most popular adjuvants, face the same issues as vaccines: their mechanism of action is still debated [160]. Newer adjuvant systems may target innate immune system signaling pathways like Toll-like receptors (TLR) to direct vaccination-induced immunity and better match pathogen-specific immunity requirements (e.g. skewing of cellular vs. humoral immunity), resulting in a longer-lasting immune response. For example, AS04, a combination of MPL (monophosphoryl lipid A) (a TLR-4 agonist) and aluminum hydroxide, is used in an HPV vaccine, TCV™. This HPV vaccine Cervarix®, when compared to Cervarix®, on the same vaccine platform (Virus-like Particle, VLP) but with only an aluminum salt (aluminum hydroxy phosphate sulfate) as adjuvant, induced a 2- to 9-fold greater antibody response but had a similar serum-antibody decay showing that ASO4 does not substantially change humoral immune response kinetics [161]. Thus, a better adjuvant system can help us achieve a ‘tailor-made’ immune response. Given the theoretical possibility of immune-mediated disease induction with such an adjuvant, caution is warranted toward safety when pursuing this approach.

6. Conclusion

Vaccination research and development have made great strides in the last two centuries, yet most vaccines have been developed empirically. We must still understand their mechanisms, especially the complicated interaction of innate, humoral, and cellular components and their subcomponents [162]. Discoveries in this field are beginning to reduce our knowledge gaps. Similarly, bioengineering technologies are evolving rapidly. With nanoparticle and virus-like particle vaccinations, antigen valence and density are finely regulated. Antigen delivery can be controlled and sustained via newer biomaterials. New adjuvants, especially mucosal ones, can activate specific innate immune pathways. As the mechanisms of immune response durability become clearer, we can construct vaccines strategically to provide durable vaccine-induced protection with fewer doses.

7. Expert opinion

Vaccines have contributed immensely to the reduction of morbidity and mortality associated with infectious diseases, and ultimately reduction in infant/under-five mortality rates, Disability Life Years (DALY), school and work absenteeism, and thus rise in productivity, the standard of living and life expectancy, We have achieved a lot despite having only a handful of vaccines that provide long term (>20 years/lifelong) protection with one or two doses; vast majority of vaccines provide protection for 7–10 years, and often require multiple doses. Quite a few vaccines provide only short-term protection (<5 years). Enhancing longevity to the vaccine-induced protection would undoubtedly act as a ‘force multiplier’ in achieving all the benefits enumerated above. Further, by helping drastically reduce the cost of immunization programs, it has tremendous direct and indirect economic benefits to the nations, adding to the reputation of vaccines in particular and medical science in general.

The last few years have seen some rapid strides in the development of vaccines. The gestation period of developing a new vaccine has been cut down significantly – from the approval of a concept to the licensing of a product. Thanks mainly to the advent of new vaccine platforms, like nucleic acid-based mRNA and DNA vaccines, coupled with the advanced knowledge of biologically active forms of antigens and their interaction with the host cell, helped experts to design more effective and potent formulations, as shown in the successful development of RSV vaccines. Some progress in ensuring vaccine-induced immunity’s longevity is also there, but it is much slower. As discussed in our review, HPV vaccines shine out in this aspect. Based on the VLP vaccine platform, they have supramolecular nanoparticles with highly repetitive antigen sequences on their surfaces that significantly promote the early B-cell activation and the persistence of GC responses, leading to enhanced long-lasting plasma cell differentiation and durable immune response. Thus, despite being inactivated vaccines, they offer long-term protection, similar to live attenuated vaccines, without needing boosters. Many other strategies are currently being hotly researched to improve the durability of vaccine protection. Tweaking conventional immunization techniques such as long-prime, slow-delivery (12 days) immunization approach is one such strategy in this direction, as demonstrated in some animal studies with experimental HIV vaccine [154] and influenza vaccine development [153].

Most currently licensed vaccines have been developed empirically with a ‘develop and then see/assess’ approach. The need of the hour is to develop vaccines strategically. Undoubtedly, there are challenges regarding our understanding of immunology and the exact correlates of long-term protection. Thus, there is a need to identify ‘protective thresholds’ for different vaccine formulations and bio-markers of protective immunity so that minimum antibody levels should be maintained above the threshold to avoid a breakthrough infection [107].

As elaborated in the review, the two vital immunological mechanisms that enhance the persistence of immune responses are memory B cell generations in the germinal centers and the survival of long-lived plasma cells in the bone marrow niches. There is a need to recognize factors that lead to the genesis and persistence of germinal centers apart from the nature and kinetics of their delivery. Similarly, identifying early innate signals that differ by agents and vaccine platforms could help develop and ensure the survival of long-lasting plasma cells in the bone marrow, providing a lasting immune response. Working on adjuvanted SARS-CoV-2 vaccine on non-human primates, Prabakaran et al. have demonstrated a sensitive method to identify and isolate antigen-specific long-lived plasma cells (LLPCs). Their published work has shown that spike protein vaccination can elicit and maintain LLPCs [163].

Targeting specific epitopes or genes in antigenic sites conserved in different variants can also ensure the durability of protection. Further, there is a need to focus beyond the measurement of antibody production and target key mucosal sites to demonstrate tissue-generated memory cells at different mucosal tissues, which may help prevent breakthrough infections and ensure longevity.

Identifying solutions to these gaps in our understanding should form the future research agenda in the vaccinology field. We are confident that we are moving slowly but surely from an era of empirically developed vaccines to that of ‘designer vaccines,’ with particular emphasis on the durability of protection. In the coming years, the vaccine industry shall be able to resolve the current shortcomings with the help of advancements in biomaterials and bio-engineering for vaccine development.

Article highlights

• Only a handful of currently licensed vaccines provide long-lasting protection

• There are still gaps in our understanding of reliable correlates of durable protection.

• Induction of vigorous germinal center reaction and induction of a large number of long-lasting plasma cells along with the formation of memory B-cells and memory T-cells is essential for durable vaccine-induced protection

• There are several determinants of the longevity of antibody response, such as vaccine platform, target pathogen, vaccinee’s characteristics, environmental and genetic factors

• New developments in the field of vaccinology, like improved vaccine design, novel adjuvants, and molecular delineation of antigenic forms, hold hope for developing durable vaccines

• Further research is needed to identify the optimal antigen delivery methods and formulations that result in prolonged antigen availability and can elicit long-lasting and protective immunity

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

VMV and PK have substantially contributed to the conception and design of the review article and interpreting the relevant literature, and been involved in writing the review article or revised it for intellectual content.

Additional information

Funding

This paper was not funded.