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What vaccines are recommended for the elderly?
Global 65 proportion and older population is increasing rapidly, infection in this age group of the population (most recently of SARS-CoV-2 ) can lead to significant morbidity and mortality.
Vaccines for the elderly have made major improvements, such as adding new adjuvants (new recombinant shingles vaccine and adjuvant influenza vaccine) or increasing the antigen concentration (influenza vaccine).
This article reviews the immune improvements of three vaccines that can prevent aging diseases. The effective rate of recombinant shingles vaccine is 90% , and it is least affected by the age of the vaccinated, and the duration can exceed four years.
Although the relative effectiveness of the enhanced influenza vaccine and the durability of the immune response are the key indicators of current clinical trials, increasing the antigen dose or adding adjuvants can improve the immunogenicity of the elderly influenza vaccine.
Conjugated vaccine and polysaccharide pneumococcal vaccine have similar effects on invasive pneumococcal diseases of the elderly and pneumococcal pneumonia caused by the vaccine serotype. The relative value varies with the environment, depending on the prevalence of the vaccine serotype, mainly It is related to the coverage of conjugate vaccines in children.
Improving vaccine efficacy can increase public confidence and acceptance of vaccines. In order to ensure the intake of vaccines for the elderly as much as possible, these vaccines can be administered in combination.
With the arrival of SARS-CoV-2 , the development of new vaccine platforms has been greatly accelerated, and new vaccines against other pathogens may be produced in the future.
In the elderly, influenza, shingles, and pneumococcal infections can cause significant morbidity and mortality (Figures 1 and 2).
Australia, Europe and Canada have similar estimates of vaccine-preventable disease burden.
Effective vaccines against influenza, pneumococcal infection, and shingles have the greatest potential for preventing morbidity and mortality in people over 65 years of age.
Figure 1 shows the estimated number of disability-adjusted life years lost each year in Australia, and Figure 2 shows morbidity and mortality for all ages.
Figure 1 The impact of influenza, shingles, and invasive pneumococcal disease (IPD) on the disability-adjusted life-years per 100,000 people by age group .
Data from the Australian burden of disease study in 2015.
Figure 2 Cases, deaths and population burden of vaccine-preventable diseases. The size of the bubble represents the population level burden (DALY/100000 people).
Data from the Australian burden of disease study in 2015.
Vaccines to prevent these diseases have long been available, however, the immune effect and durability are not ideal (especially in people 70 years and older).
But as evidenced by the efficacy (~90%) of the recombinant shingles vaccine (RZV), the effectiveness of the vaccine can be improved.
Because seasonal flu vaccines are less effective for people 65 years of age and older, flu and pneumococcal vaccines need to be improved.
This article analyzes the current evidence for maximizing influenza, pneumococcal disease, and shingles vaccines for adults 60 years of age and older, and identifies potential directions for future research.
Varicella-zoster virus-specific cell-mediated immunity declines with age (immune senescence) and decline in immune function, increasing the frequency and severity of herpes zoster infection. An 85-year-old person has a 50% lifetime risk of infection; in the United States and Australia, two-thirds of cases occur in people 50 years or older.
Type A and Type B influenza viruses cause seasonal epidemics of human influenza. Currently, two influenza A virus subtypes (A/H1N1pdm09 and A/H3N2) and two influenza B lineages (B/Victoria and B/Yamagata) can cause seasonal influenza epidemics individually or together.
Seasonal influenza A and B viruses continue to evolve in nature, usually leading to antigen changes or “drift”. The components of the flu vaccine are updated once a year to keep up with the pace of antigen drift. A
dults 65 years of age or older are at the highest risk of hospitalization, complications, and death due to influenza, and those over 85 have a significantly increased risk of hospitalization, complications, and death.
It is estimated that the global average annual mortality rate of respiratory tract associated with influenza is 0.1-6.4/100,000, 0.1-6.4/100,000 for those under 65, and 17.9-223.5/100,000 for people over 75.
This wide variability is due to annual differences in virus strains and the severity of related diseases. However, non-respiratory deaths are often not included.
The age-specific incidence of invasive pneumococcal disease (IPD) is U-shaped, with a peak at <2 years old and >85 years old. In the United Kingdom and the United States, the incidence of chronic diseases (especially weakened immune function) will increase.
Among the placebo recipients of the CAPiTA vaccine trial in the Netherlands, the detection rate of community-acquired non-bacteremic pneumococcal pneumonia (NBPP) in people 65 years of age or older was five times that of IPD. In a region of the United Kingdom, NBPP gradually increased from the age of 65.
Among people over 85 years old, the incidence rate per 100,000 people is five times (349) that of 65-74 years old (60), which is similar to CAPiTA and much higher.
The estimated incidence of IPD in the UK during the same period is 27.6 per 100,000 people over 65 years of age.
Immune senescence refers to the increase in the incidence and severity of common infectious diseases (including herpes zoster, influenza and pneumococcal disease) as well as the prevalence of cancer and autoimmune diseases with increasing age (especially after 60 years of age) Increased and poor immune response.
The decline in immune methods can cause innate immune function defects, such as natural killer cells, (monocyte-derived) dendritic cells and polymorphonuclear leukocytes.
At the same time, adaptive immunity will decrease-the diversity of initial T cells and B cells will decrease, T cell memory will decrease, B cell memory will decrease, and the differentiation of B cells into plasma cells will decrease. With age, lymph nodes shrink and become fibrotic, limiting the migration and encounter of dendritic cells, T cells, and B cells.
The pathogenesis and significance of herpes zoster
Shingles is caused by the reactivation of varicella-zoster virus from the latent state of the dorsal root and cranial nerve sensory ganglia.
Varicella-zoster virus-specific T cell-mediated immunity can prevent or control the reactivation of latent varicella-zoster virus.
When the immunity mediated by varicella-zoster virus-specific T cells drops below a certain critical threshold, the reactivated varicella-zoster virus can damage neurons and cause ganglionitis, leading to the affected skin area There is neuropathic pain.
The reactivated varicella-zoster virus also transports anteriorly in the affected sensory nerves to the skin, causing pathological rashes and nociceptive pain.
The typical shingles rash evolves from erythema papules to blisters and scabs within 7-10 days and heals within four weeks; the pain that may precede the rash is usually severe.
Complications of shingles increase with age and impaired immune function. The immune function mediated by varicella-zoster virus-specific T cells decreases with age, which is closely related to the incidence of shingles and the severity of pain.
Among people over 50, 15% of people have pain that lasts for at least three months. Post-herpetic neuralgia is the most common complication of herpes zoster.
Its frequency, severity, and duration increase with age (usually after the age of 50).
Post-herpetic neuralgia cannot be prevented by antiviral therapy, and this pain is difficult to treat, especially for elderly patients.
Other complications of shingles include about 10% of eye infections (about 1.5% of uveitis), bacterial superinfection (2-5%) and disseminated diseases in immunodeficiency patients, and neurological complications such as Cerebral arteritis and stroke, Ramsay-Hunt syndrome, myelitis, motor neuropathy and encephalitis are rare complications.
Live attenuated shingles vaccine (ZVL)
The well-recognized relationship between varicella-zoster virus-specific T cell-mediated decline in immunity and increased incidence and severity of herpes zoster, prompting the use of Oka (Merck) attenuated varicella-zoster virus strain can be significant In addition, experiments to safely improve the immunity mediated by varicella-zoster virus-specific T cells in the elderly are carried out. 38,500 immune-competent elderly people over the age of 60 were vaccinated with a research vaccine for shingles containing 19400 pfu (14 times higher than varicella vaccine) of the virus, this varicella-zoster live attenuated vaccine (ZVL; Zostavax) ) The effective rate of preventing herpes zoster is 51.3%, and the effective rate of preventing post-herpetic neuralgia is 66.5% (Table 1a). However, the statistically significant effect of age is obvious-at the time of vaccination, the effective rate is 63.9% for people aged 60-69, 41.0% for people aged 70-79, and older vaccinators are more effective. Low.
In addition, the long-term follow-up of the efficacy trial showed that the efficacy of the vaccine decreased significantly 4-8 years after vaccination.
This was confirmed in an effectiveness study, but was not proven in another large study-in this study, the protection rate of shingles remained at 47.2-41.0% for at least four years.
The protection rate of neuralgia after herpes is maintained at 60-70%, and has nothing to do with the age at the time of vaccination.
Another limitation of ZVL is that as a live attenuated vaccine, it is contraindicated in patients with moderate to severe immune function due to fear of spreading and/or fatal diseases.
Despite these limitations, ZVL is still an important step forward. It is the only shingles vaccine approved for use in elderly people over 50 years of age with immune function in many countries, although national recommendations and project funding usually limit its use to the elderly population. In addition, ZVL has an important soothing effect (even when shingles occurs), so 67% of vaccinators over 70 years old can prevent post-herpes zoster neuralgia, and to a large extent maintain the elderly vaccinators Quality of life after contracting shingles.
In the United Kingdom, ZVL is recommended for 70-year-old adults, and its catch-up plan is 71-79 years old.
After three years, the coverage rate of the first regular cohort is 72%, and the coverage rate of the catch-up cohort after three years is 58%.
In this case, the shingles vaccine is estimated to reduce the incidence of shingles by 35% and the incidence of post-shingles neuralgia by 50%.
Another study found that the level of efficacy of the vaccine against shingles was similar.
Attempt to improve the clinical characteristics of ZVL
Due to the lack of specific immune substitutes for protection, measures to overcome the limitations of ZVL have become complicated.
Antibody levels before and after shingles vaccination and varicella-zoster virus-T cell-mediated immunity are related to population protection.
However, except for the five-fold increase in the antibody titer of varicella-zoster virus six weeks after vaccination, which can predict a protection rate of 90% for individuals aged 50-59 years, there is no prediction of protection for individual vaccinators.
Neither increasing the concentration of the vaccine virus nor giving two doses of the vaccine can improve the immunogenicity of the vaccine.
Compared with age-matched first-time vaccinators, some people were re-immunized ten years after the first immunization, resulting in a significant increase in the level of immunity mediated by varicella-zoster virus-specific T cells.
As a result, the trend of declining immunity has been reversed, even superimposed with the increase in immunity mediated by varicella-zoster virus-specific T cells from the initial vaccination, which lasts at least for three years.
Long-term vaccine safety
A 10-year vaccine safety review after 34 million doses of vaccination reported 23,556 adverse events, 93% of which were not serious.
Seven cases of vaccine-related serious diseases, including disseminated diseases and three deaths, occurred in immunocompromised patients, which emphasized the importance of avoiding the administration of ZVL to severely immunocompromised patients.
Recombinant shingles subunit vaccine ( RZV )
The more effective shingles subunit vaccine (Shingrix; RZV) consists of recombinant varicella-zoster virus glycoprotein E (gE) and AS01B adjuvant system.
Glycoprotein induces gE-specific immune responses, and AS01B shapes these responses. AS01B consists of QS21 (a saponin extracted from a purified extract of cress) and toll-like receptor 4 (TLR4) agonist monophosphate lipid A (MPL); both are contained in liposomes.
AS01B stimulates gE-specific CD4+ T cells and antibody responses in animal models. Similar adjuvants have been used with many pathogens, including herpes simplex virus, hepatitis B and malaria, with partial success.
Varicella-zoster virus gE was chosen because it is the most abundant glycoprotein on varicella-zoster virus-infected cells, and it is also the main target of varicella-zoster virus-specific antibodies and T cells. RZV can also induce virus neutralizing antibodies.
In phase I/II clinical trials, testing the combination and concentration of antigen and adjuvant in elderly people over 50 years old showed that the adjuvant system added to recombinant gE is better than gE-specific CD4+ T cells and antibodies induced by glycoprotein alone The response is stronger.
This is obvious regardless of age. Two months after the first administration, the second administration of gE/AS01B can increase the frequency of VZV-specific CD4+ T cells and antibody levels by about 30%, providing two dose plans for the phase III trial.
The effect of RZV on the onset of herpes zoster (table 1b , 1c )
Two randomized, blinded, placebo-controlled phase III clinical trials of RZV were conducted simultaneously in 18 countries (five continents), and the subjects were adults over 50 years old (age ≥50 years of adult herpes zoster efficacy study, [ZOE- 50]) and adults over 70 years old ([ZOE-70]). In ZOE-50, participants are between 70-79 years old and ≥80 years old.
These two trials have determined the effectiveness of preventing shingles infection, vaccine safety and reactogenicity in the entire study population and in each age group.
The ZOE-70 trial aims to better determine the efficacy of shingles and post-herpetic neuralgia in elderly people ≥70 years of age, because these two conditions are more common in this age group.
Herpes zoster is confirmed by polymerase chain reaction (PCR) of varicella-zoster virus DNA (90%) lesion swabs; if the diagnosis is not clear, it is confirmed by checking the clinical report and photos. In ZOE-50, 210 people in the placebo group (9.1/1000 person-years) and 6 people (0.3/1000 person-years) in the vaccine group had shingles (97.2% vaccine efficacy).
The efficacy of all three age groups was similar (Table 1a) and continued to be effective for a median of 3.2 years in the study, and then for more than 7 years during the extended period of these trials. The efficacy is similar in different parts of the world. In ZOE-70, 223 placebo and 23 vaccine recipients developed shingles (vaccine effective rate 89.8%).
Unlike ZVL’s age effect, the 70-79-year-old age group (90.0%) and the 80-year-old age group have similar effects (89.1%; P<0.001), while the effective rate for the two trials pooled elderly people over 70 years old It was 91.3%.
Efficacy of RZV on neuralgia after herpes zoster
The aggregated data from ZOE-50/70 show that the incidence of post-herpetic neuralgia in placebo and vaccinated patients was 0.9 and 0.1 cases per 1000 person-years, respectively, and the curative effect on post-herpetic neuralgia was 91.2% ( 95% confidence interval, 75.9-97.7%).
No cases of post-herpetic neuralgia have been recorded in people younger than 70 years old.
The incidence of post-herpetic neuralgia in patients with herpes zoster was similar between placebo and vaccinators (12.5% vs. 9.6%, P=0.54), indicating that RZV mainly prevents herpes zoster rather than alleviates post-herpetic nerves Pain to prevent neuralgia after herpes zoster, as in ZVL.
The lack of age effects of RZV on herpes zoster and post-herpetic neuralgia is important because the incidence and severity of both increase significantly with age in the unvaccinated population.
Although the incidence of shingles varies among different genders and ethnic groups, no such differences have been observed in the efficacy of RZV.
Safety, reactogenicity and tolerability of RZV
Compared with most other vaccines, RZV is associated with more injection sites and systemic reactions within 7 days after administration, and may be disabling (Table 2). Myalgia, fatigue, and pain at the injection site are the most common reactions at any dose.
Grade 3 injection site reactions (impairing daily activities, similar to the definition in the general term standard for adverse events) were reported in 8.5-9.5% of vaccinators; 6-11% reported grade 3 systemic reactions.
Both systemic and local reactions were short-lived (1-3 days), and there was no significant difference between the first and second administration.
Most subjects (66%) who had a grade 3 response after the first dose had a lower grade response after the second dose. In the elderly and infirm over 80 years old, local and systemic reactions are rare.
The vaccine response did not prevent 96% of participants from receiving a second dose of the vaccine. The adjuvant system AS01B was shown to be mainly responsible for reactogenicity in the Phase II RZV trial.
No new immune-mediated diseases or exacerbations of old diseases were detected in RZV subjects. There was no difference between the vaccine group and the placebo group in terms of serious adverse events or deaths.
The safety and immunogenicity of RZV are similar to those who have had shingles in the first five years of RZV.
Immunogenicity of RZV
In the ZOE trial (and the previous phase II) trial, RZV induced a significant increase in cell-mediated immunity and humoral immunity without age effects (Table 3).
Almost all vaccine recipients showed a significantly higher antibody response than the baseline level.
The geometric mean concentration of anti-gE antibody reached a peak one month after the second administration and stabilized at 12-36 months.
A statistically significant increase in the frequency of gE-activated CD4+ T cells was observed in >90% of RZV subjects.
The peak CD4+ T cell response of RZV subjects also appeared 1 month after the second administration, and decreased at 12 months in all age groups, but stabilized at 36 months and was significantly higher than baseline level.
Early decline was observed in CD4+ T cells with a single function, but at 36 months in all age groups, CD4+ T cells with multiple functions persisted.
In particular, the interleukin-2 response is retained. The immune relevance of protection could not be determined in the ZOE-50/70 trial because there are very few cases of shingles in RZV subjects.
When comparing the immune responses of 50-85-year-old participants to ZVL and RZV, after RZV administration, the frequency of VZV and gE-specific T cells was higher; after RZV administration, gE-specific CD4 and CD8 effects and memory Sex T cell response is more than 10 times higher, and the peak response of RZV subjects can roughly predict its subsequent persistence.
The response of gE-specific T cells to RZV has been higher than the baseline level for at least nine years.
The most important immunological principle derived from the Phase I/II and III trials is that a single viral protein combined with an appropriate adjuvant provides strong protection against shingles in the elderly and immunocompromised people for many years.
This may be because varicella-zoster virus gE is an excellent immune target for stimulating CD4+T cell responses, and AS01B enhances the gE-specific memory immune response.
The mechanism of action of AS01B in RZV
In a mouse model, AS01B intramuscular injection and draining lymph nodes stimulate the local innate immune response, leading to the recruitment and activation of antigen-presenting dendritic cells in the lymph nodes.
These cells take up and present gE to CD4, CD8 T cells and B cells (Figure 3). MPL works synergistically with QS-21 to enhance the response of antibodies and T cells to gE.
Figure 3 The mechanism of action of AS01B in mouse lymph nodes
Initially, QS21 stimulated peripheral (sinus wall) macrophages to release interleukins 12 and 18, thereby stimulating natural killer cells to release interferon gamma.
This attracts monocyte-derived dendritic cells to the lymph nodes and activates them and the resident dendritic cells through MPL.
Then, dendritic cells present the gE antigen to T cells and B cells. Encapsulation of MPL and QS21 in liposomes can enhance cellular uptake and reduce toxicity.
After immunization with RZV, the components of the cascade reaction, especially interferon-γ, have been identified in the lymph nodes of primates and/or human blood.
Efficacy, reactogenicity and safety of RZV in patients with complications
In addition to immunosuppressive diseases and medications, other diseases may increase the risk of shingles, such as rheumatoid arthritis and inflammatory bowel disease.
In the ZOE trial, about 82% of subjects had at least one type, and most of them suffered from multiple complications.
The effectiveness of the vaccine does not change with the presence of any pre-disease conditions or multiple conditions (up to six).
Immunization for immunocompromised patients
The incidence and severity of herpes zoster are increased in immunocompromised patients, and they are all proportional to the degree of immunocompromised.
Patients receiving allogeneic or autologous hematopoietic stem cell transplantation (HSCT) are particularly susceptible, with the incidence of shingles in the first year after transplantation being 15-30%.
The risk of untreated HIV-infected people suffering from shingles is 10 to 20 times higher than that of people of the same age, and the risk is still 2 to 3 times higher after receiving antiretroviral therapy.
Complications of shingles (including recurrent episodes) are approximately three times higher in HIV-infected persons. Live attenuated vaccines such as ZVL are banned under the following conditions that can cause severe immune damage-HIV with a CD4 count of <200/µL, the use of high-dose corticosteroids and other immunosuppressive therapies, and after HSCT or solid organ transplantation.
In these cases, infectious vaccine strain infections and deaths occurred. The safety and effectiveness of ZVL in the case of less immune damage are currently being determined, such as the treatment of autoimmune diseases with biological agents (including tumor necrosis factor inhibitors).
If feasible, ZVL can also be used before chemotherapy or transplantation.
Five clinical studies of RZV have been reported in immunocompromised patients (Table 4), and each study has demonstrated its safety.
Trials conducted in patients receiving autologous HSCT transplantation and patients receiving chemotherapy for malignant hematological diseases have confirmed the efficacy.
In three smaller trials, substantial immunogenicity was observed in HIV patients (mostly with substantial recombination) after kidney transplantation or chemotherapy for solid tumors.
In kidney transplantation studies, no vaccine has been found to have an effect on allograft rejection. Solid tumor studies have confirmed that if the vaccine is not vaccinated during chemotherapy, the immune response is the best.
A number of autoimmune diseases (such as multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis) related trials are underway, and biomodulators are used.
It is meaningful to comprehensively compare the safety and effectiveness of RZV and ZVL in diseases that cause mild to moderate immunosuppression (such as autoimmune diseases) or in the treatment environment.
In particular, the effects of additional therapies that inhibit the response of CD4 T cells to RZV also need to be tested.
The current research aims to understand the exact mechanism of AS01B adjuvant in humans-based on past animal model studies, to study how to reduce reactogenicity while maintaining immunogenicity.
Influenza viruses are enveloped viruses whose RNA genome consists of eight gene segments that encode one or more proteins. Influenza A and B viruses can spread and cause influenza in all age groups. Early childhood exposure to influenza virus.
The first exposure to influenza virus affects the immune system’s response to influenza vaccination in the future, and recalls the generation of antibodies to influenza virus strains experienced earlier, the so-called “primitive antigenic sin.”
Influenza A viruses are divided into different subtypes according to their main surface glycoproteins, hemagglutinin and neuraminidase.
Influenza A viruses include 18 HA and 11 NA subtypes, which infect animals including birds, pigs, horses, and bats.
Only three hemagglutinin subtypes (H1, H2, and H3) and two neuraminidase subtypes (N1 and N2) are responsible for the continued epidemic of human influenza.
The diversity of influenza B viruses is relatively limited, divided into two lineages.
Antigen drift and antigen transfer
There are two mechanisms for the antigenic change of influenza virus: antigenic drift and antigenic transfer.
In influenza A and B viruses, antigenic drift is a continuous process.
Point mutations in hemagglutinin and neuraminidase proteins allow the virus to escape the neutralization of antibodies caused by previous infections or vaccination.
In contrast, antigen transfer is a major antigenic change-when a virus carrying a new type of hemagglutinin (with or without a new neuraminidase) and/or from another species (usually a bird or pig) When the concomitant gene fragments of influenza A virus are introduced and established in humans, antigen transfer occurs.
A pandemic occurs when a new influenza A virus (to which most of the population lacks immunity) crosses the species barrier, causes disease, and spreads from person to person through a continuous chain of community-wide transmission.
Influenza pandemics rarely occur irregularly.
The most recent pandemics occurred in 1918, 1957, 1968 and 2009. They can be caused by animal influenza viruses directly infecting humans or by recombination between animal influenza viruses and previously transmitted human influenza viruses.
The response to an influenza pandemic requires the development of new influenza vaccines.
Influenza infection mainly induces protective systemic and mucosal antibody responses to hemagglutinin and neuraminidase surface glycoproteins. “Follicular helper” CD4+ T cells are also stimulated to maintain antibody production.
CD8+ T cells that recognize the highly conserved internal virion protein can lyse infected cells and secrete cytokines to clear the virus and reduce the severity of the disease, but cannot prevent infection.
Therefore, the basic principle of the currently licensed influenza vaccine to prevent infection is to induce protective antibodies against hemagglutinin; hemagglutination inhibition (HAI) titer is a relevant parameter for protection.
Effectiveness and composition of approved vaccines
The currently approved seasonal influenza vaccines are multivalent and contain antigens representing two prevalent influenza A subtypes and one or two prevalent influenza B virus lineages.
The standard influenza vaccine is a trivalent or quadrivalent preparation consisting of inactivated split virus particles, rich in hemagglutinin and neuraminidase, and formulated into hemagglutinin containing 15μg of each virus component.
The effectiveness of influenza vaccine depends on many factors, including antigen matching between epidemic strains and vaccine strains, adaptive mutations caused by the growth of vaccine viruses in chicken embryos, and age.
As shown in Table 5 (for the United States), the effectiveness of influenza vaccines has been low in the past few years.
According to the epidemiological and virological monitoring conducted by the World Health Organization’s Global Influenza Surveillance and Response System, the composition of seasonal influenza vaccines (including antigen and genetic characteristics) are updated every year, and predictions are made based on the model of hemagglutinin sequence.
There are three key challenges when selecting viruses for seasonal flu vaccines. First, there is considerable genetic heterogeneity among influenza A viruses circulating globally.
The currently approved influenza vaccine can induce strain-specific immunity, and viruses from different genetic branches do not elicit cross-reactive antibodies.
Improve the breadth of vaccine-induced immunity should be prioritized for research, including the design of extensive cross-reactive hemagglutinin, standardization of the amount of neuraminidase, the addition of adjuvants, and the development of general influenza vaccines.
Second, since the production and delivery of the vaccine takes several months, the vaccine strain was selected about six months before then.
During this period, influenza viruses continue to evolve, so it is particularly important to explore better prediction methods.
Third, most of the global supply of influenza vaccines is produced from chicken embryos.
Chicken embryo adaptation mutations caused by vaccine virus growth in chicken embryos can change the antigenic properties and glycosylation of hemagglutinin protein.
In some countries, vaccines produced in qualified cell lines and recombinant hemagglutinin protein vaccines can be used, both of which can prevent chicken embryos from adapting to mutations.
Regardless of its composition, the immunogenicity and efficacy of standard influenza vaccines in the elderly are always lower than in the young. Vaccine developers have used two strategies to develop “enhanced” vaccines for the elderly. The principle is to enhance the immunogenicity of the vaccine and then improve the efficacy of the vaccine.
The first is to increase the vaccine dose, because the high-dose vaccine contains four times the hemagglutinin of the standard dose vaccine, or the recombinant hemagglutinin (rHA) (tri-) vaccine expressed using a baculovirus vector. The second strategy uses an adjuvant (MF59 adjuvant vaccine).
Before the enhanced quadrivalent vaccine is available, the elderly should be vaccinated with the enhanced trivalent vaccine instead of the standard dose of the quadrivalent vaccine, because the increase in immunogenicity is more important than the addition of two influenza B viruses to this age group .
Unlike young children, the elderly will develop cross-reactive influenza B antibodies after exposure to influenza B virus.
Fluzone high-dose TIV contains 60 μg of each hemagglutinin. Both men and women have greater response to the high-dose vaccine than the standard-dose vaccine.
Post-mortem analysis found that in older participants, the immunogenicity of the high-dose vaccine was improved, and it was maintained in people over 75 years of age and patients with chronic heart or lung diseases (Table 6).
Table 6 High-dose influenza vaccine
The US Food and Drug Administration approved a high-dose trivalent vaccine for the elderly in 2009 and requested data on the vaccine’s effectiveness in preventing influenza in the elderly.
A Phase IIIb/IV study conducted on nearly 32,000 elderly people during two flu seasons showed that using high-dose vaccines instead of standard-dose vaccines can prevent about one-quarter of outbreaks of influenza disease and one-third of causes An outbreak of disease caused by similar strains in the vaccine.
In a separate randomized study or a meta-analysis of randomized and observational studies, the number of people who need high-dose vaccines instead of standard doses to prevent all-cause hospitalization is 52.6 to 71.4; nursing home residents from 68.7 to 83.7 need high-dose vaccines , Instead of a standard dose of vaccine to avoid a hospitalization.
High-dose vaccines are cost-effective and may save costs in the elderly. The model shows that the transition from standard doses to high-dose trivalent vaccines in the United States will prevent 195,958 flu cases, 22,567 flu-related hospitalizations, and 5,423 flu-related elderly deaths, while shifting from standard-dose quadrivalent vaccines to high-dose trivalent vaccines The vaccine will prevent 169,257 flu cases, 21,222 flu-related hospitalizations, and 5,212 flu-related deaths.
Taking into account the cost of vaccines and the reduction in utilization of medical care, high-dose trivalent vaccines are more cost-effective than standard-dose trivalent or quadrivalent vaccines.
The analysis of the data from the Phase IIIb/IV trial estimates that the average medical cost per subject in the high-dose trivalent group is about 116 dollars lower than that of the standard-dose trivalent group.
Compared with the standard-dose trivalent vaccine, the high-dose trivalent vaccine also saves costs ($12) in participants with one or more complications ($106) and elderly people over 75 years of age.
MF59 is an oil-in-water adjuvant containing squalene, and its mechanism of action is not yet fully understood.
MF59 triggers immune stimulation by indirectly activating cytokines in dendritic cells. MF59 enhances the recruitment and activation of immune cells at the injection site, and enhances the uptake of antigen by antigen-presenting cells and their transport to draining lymph nodes.
MF59 induces the release of ATP outside muscle cells, which is a “danger signal” that can enhance antibody response to co-administered antigens.
The magnitude, breadth, diversity and affinity of hemagglutinin antibodies of the elderly who received the MF59 adjuvant influenza vaccine were higher than those of the elderly who received the standard dose.
After the MF59 adjuvant vaccination, the geometric mean titer of hemagglutinin-inhibiting antibodies was higher, and the antibody titer increased fourfold; these differences persisted for six months after vaccination.
The MF59 adjuvant vaccine has a wider range of antibody response and higher antibody titers against antigen drift strains.
The adjuvant antibody library shows that the proportion of anti-hemagglutinin antibodies against the HA1 receptor binding domain is higher than that of the dry region where antigenicity is not important.
A systematic review of 11 observational studies involving more than 546,000 people-seasons showed that the MF59 adjuvant vaccine can effectively prevent hospitalization of various influenza complications and is superior to standard vaccines.
The MF59 adjuvant vaccine is also effective for elderly people living in communities and long-term care facilities (Table 7).
Recombinant hemagglutinin vaccine
Recombinant hemagglutinin (rHA) vaccine is a highly purified product. Each strain contains 45μg of recombinant hemagglutinin, which is three times the content of hemagglutinin in the standard vaccine.
It is worth noting that the rHA vaccine does not contain neuraminidase, which avoids the presence of chicken embryo protein.
In a randomized controlled trial of trivalent rHA compared with a standard dose of trivalent vaccine, the geometric mean titer of serum hemagglutinin inhibitory antibodies and the seroconversion rate of anti-influenza A antigens were significantly higher in the rHA group.
These differences are more pronounced in elderly people over 75 years of age.
In a multi-center randomized controlled trial of a quadrivalent recombinant influenza vaccine (RIV4) compared with a standard-dose quadrivalent vaccine, RIV4 provided better protection against laboratory-confirmed influenza-like diseases in people over 50 years of age.
Compared with the tetravalent vaccine, RIV4 has a 30% lower probability of influenza-like illness (95% confidence interval, 10-47%; P=0.006).
However, the relative effectiveness of the vaccine in the subgroup of participants over the age of 64 (17%, 95% confidence interval, -20-43%) was lower than that of the 50-64 age group (42%, 95% confidence interval, 15- 61%) participants. The safety characteristics of the vaccine are similar.
Comparison of enhanced vaccines
There are several studies comparing the effects of enhanced vaccines and standard-dose vaccines in the elderly, but few comparisons of enhanced vaccines have been made.
In a systematic review of 39 randomized controlled trials, high-dose or adjuvant vaccines and standard doses (selection, reports, and other sources) were compared in elderly people over 60 years of age with a low risk of bias, and there were sufficient and complete results data , Indicating that the enhanced vaccine induces a higher antibody response than the standard dose vaccine.
In the trial of contrast-enhanced and standard-dose vaccines, the increase in geometric mean titer of anti-A (H3N2) after vaccination with high doses (82%, 95% confidence interval, 73-91%) was significantly greater than that of the MF59 adjuvant vaccine ( 52%, 95% confidence interval, 35-72%).
The titer ratio after high-dose vaccination was significantly higher than that of the MF59 adjuvant vaccine (P=0.04). For A (H1N1) and B/V viruses, the geometric mean titer after high-dose vaccination is also higher than that of the MF59 adjuvant vaccine.
Vaccine safety: A randomized controlled trial comparing the results of three enhanced vaccines (MF59 adjuvant TIV, high-dose trivalent or quadrivalent RHA) and standard-dose quadrivalent vaccine among 65-82-year-olds living in Hong Kong communities Show that all minor and local adverse events of influenza vaccine injection are common.
Compared with the standard-dose vaccine, some acute local reactions of the MF59 adjuvant and high-dose influenza vaccine were more frequent, and the frequency of systemic symptoms was similar in all groups.
Vaccine immunogenicity: Compared with standard dose vaccine recipients, the body fluid and cell-mediated immune response of enhanced vaccine recipients has improved. Compared with the standard-dose quadrivalent vaccine (42%), the proportion of participants with all enhanced vaccines (range 59-60%) increased by ≥ four times to titers ≥ 40 was significantly higher.
Compared with the standard dose group (72%), the proportion of participants with titers ≥40 in the MF59 adjuvant group (82%) and the high-dose group (83%) was higher. In addition, compared with the standard dose vaccine (35%), the proportion of all enhanced vaccines (45-55%) reaching very high titers (160) has increased significantly.
Compared with the recipients of the standard dose vaccine, the recipients of the enhanced vaccine obtained a higher geometric mean titer after vaccination and a higher average multiple of A (H3N2) antigen.
In the enhanced vaccine, the antibody response of the tetravalent rHA subjects to the A/H3N2 strain was significantly higher than that of the standard dose vaccine, MF59 adjuvant and high-dose subjects.
The immunogenicity of all three enhanced vaccines was significantly higher than that of the standard dose vaccine.
Therefore, they can improve the immune response induced by vaccines in the elderly.
After 30 days of vaccination, compared with the MF59 adjuvant vaccine, the antibody response at high doses (rHA and high dose) was significantly enhanced, but its duration needs further study.
The relative effectiveness of high-dose vaccines in preventing influenza disease requires large-scale efficacy trials to guide future decisions.
Streptococcus pneumoniae is a gram-positive bacteria commonly found in the nasopharynx. It causes diseases (pneumonia, otitis media, and sinusitis) by extending from the nasopharynx or entering the bloodstream, and spreads to normal sterile parts such as Alveoli, meningeal cavity, or joint fluid (invasive pneumococcal disease [IPD]).
The polysaccharide capsule on the surface of pneumococcus becomes the main cause of disease by preventing the opsonization of complement and subsequent phagocytosis.
There are more than 90 capsular serotypes of Streptococcus pneumoniae, and each serotype is characterized by its specific polysaccharide molecular structure.
Serotypes have differences in colonization and invasion capabilities, so each serotype can be regarded as a unique pathogen; the specificity of serotype antibody protection emphasizes this point.
Although antibodies against certain serotypes provide cross-protection (6B against 6A and 6A against 6C), this is not the case for other serotypes (such as 19F and 19A).
Pneumococcal Polysaccharide Vaccine (PPV)
Experiments conducted on adults in the early 20th century showed that the pneumococcal capsular polysaccharide vaccine has a good effect, but it has been replaced by penicillin. However, the infant’s antibody response to polysaccharide antigens is transient and variable. In the 1970s, a 23-valent polysaccharide vaccine (23vPPV) was developed and has remained unchanged since it was approved in the United States in 1989. Although there is consistent evidence of protection against IPD (especially in susceptible adults), the protection against IPD-free pneumonia has been uncertain due to the lack of sensitive and specific diagnostic tests.
Pneumococcal Conjugate Vaccine (PCV)
The first randomized controlled trial of a pneumococcal conjugate vaccine was completed in the late 1990s.
The vaccine combines the seven most common serotypes in the United States with mutant diphtheria toxin (CRM157), and it is available for all seven serotypes in children under 2 years of age. Significant curative effect.
With the widespread use of PCV in infants in the United States, evidence of the accompanying “indirect” reduction in adult IPD helps determine the cost-effectiveness of PCV.
Other high-income countries have accelerated the use of PCV in children, first at 7 and then at 13, leading to a significant reduction in pneumococcal disease caused by vaccine serotypes in children and adults except for serotype 3.
However, because the vaccine serotype has been replaced by other serotypes, especially in adults over 65, the indirect reduction of adult diseases makes the incremental benefits of direct immunization in adults become uncertain.
Due to reasons that are not fully understood, the degree of substitution varies from country to country.
Table 8 shows the serotypes of two pneumococcal vaccines licensed for adults: 13-valent conjugate and 23-valent polysaccharide. The conjugate vaccine currently undergoing clinical trials contains 15 and 20 serotypes.
Immune response important for protection
The importance of determining the protective relevance of functional antibodies as a pneumococcal vaccine was first demonstrated by 7-valent PCV, in which, although IgG antibodies against serotype 19F measured by an enzyme-linked immunosorbent assay (ELISA) were in vitro with antibodies against 19A Cross-reaction occurs, but it has nothing to do with clinical protection.
Compared with ELISA, 19A and 19F opsonophagocytic assays (OPA, now the gold standard for measuring seroprotection) are indeed related to clinical protection.
However, ELISA is effective for many serotypes and has a higher degree of standardization.
A systematic analysis of five randomized trials comparing the geometric mean titers of OPA antibodies of 23vPPV and 13vPCV serotypes (including 4561 vaccinators over the age of 50).
In people over 65 years old, except for types 3, 7F and 14, all 13v serotypes have significantly higher OPA results than 23vPPV one month after 13vPCV.
The serotype-specific responses of the 50-64 year-old population to these two vaccines are more different. There was no difference in local and systemic responses between PCV13 and 23vPPV.
Cell (especially CD4 T cell)-mediated immunity plays an important role in preventing pneumococcal infection in human and mouse models.
Studies on aging mice indicate that more pneumococcal antigens may be needed to induce CD4 T cell responses, and more research is still needed.
Mucosal immunity may be important in preventing non-bacteremic pneumococcal pneumonia, especially in the elderly, but there are few studies on pneumococcal vaccines.
In randomized controlled trials comparing polysaccharide vaccines and conjugate vaccines, there were no significant differences in local or systemic reactions.
The PCV13 group had fewer severe local reactions than the PPV23 group (relative risk 0.51; 95% confidence interval 0.29 to 0.90), but among people who had never been vaccinated with pneumococcal vaccine, the local reactions in the PCV13 group were significantly more common (relative Risk 1.15; 95% confidence interval 1.05 to 1.26).
The frequency of local reactions is associated with higher antibody titers, which is consistent with a stronger immune response from the vaccine.
Vaccine potency and effectiveness
Pneumococcal polysaccharide vaccine
For IPD, 17 studies and 6 meta-analysis found that 23vPPV has significant effectiveness, although some studies are limited by the small number of cases and inclusion criteria.
As the age over 65 years old (especially over 85 years old, which is the age group with the highest incidence), the efficacy decreases.
In the largest observational study on the effectiveness of IPD vaccines, including nearly 10,000 cases in the United Kingdom, the effectiveness of vaccines for people over 65 years of age with immunocompromised functions is low and insignificant; it accounts for high-risk immune-competent people aged 65-84 53-63%; among those without risk factors, the effectiveness of the vaccine is significant even in people over 85 years of age.
It is important to note that although the effectiveness of the vaccine will decrease if 23vPPV is vaccinated before 5 years, it is still statistically significant, and because the serotype contained in 23vPPV instead of the serotype contained in PCV13 proves that the vaccine is effective against IPD Significantly effective.
A small Korean hospital case-control study conducted under the condition of high children’s PCV13 coverage also found that due to the unique serotype of 23vPPV, the vaccine’s effectiveness against IPD is very high (78%; 95% confidence interval, 34.6-92.6).
Whether 23vPPV should be used in a single dose or repeatedly has been controversial.
A meta-analysis of the 23vPPV revaccination study found that the long-term antibody response and safety of the second dose were comparable to the first dose, but the study lacked clinical endpoints, so the effectiveness could not be determined.
For non-bacteremic pneumonia, a Japanese study used a sensitive and specific diagnostic method that can identify all 23 vaccine serotypes to evaluate the effectiveness of 23vPPV for the first time.
This study was carried out in the context of the existing children’s PCV7 (not PCV13) program, using a negative test method, that is, serotype-specific PCR or urine pneumococcal test to determine all serotypes of respiratory tract samples Combination (Binax Now); the control group was negative in both analyses (Table 8).
Although the effectiveness of the vaccine against all pneumococcal pneumonia is significant, serotype-specific data show that the effectiveness of the serotype contained in 13vPCV (27.4%; 3.2-45.6%) is higher than that of the serotype contained in 23vPPV but not contained in 13vPCV Type (12.0%; -62.8-52.4%).
The protection time is estimated to be 1-2 years after PPV. The previously mentioned Korean study identified non-bacteremic pneumococcal pneumonia (NBPP) through clinical and radiological criteria and the identification of pneumococcal bacteria in sputum or urine, but lacked serotype data. In people aged 65-74, the vaccine efficacy is 35% (2.3-56.7%), but for people over 75 years of age, the vaccine efficacy is low and not significant (13%; 5-18%).
Pneumococcal conjugate vaccine
A large-scale randomized controlled trial of CAPiTA with nearly 85,000 participants provided high-quality evidence of vaccine effectiveness.
The study used a new type-specific urinalysis method to identify non-bacteremic community-acquired pneumonia (CAP) caused by the PCV13 serotype, and a non-specific urine pneumococcus analysis method (Binax Now).
As shown in Table 9, a total of 1843 CAP cases were found, of which 309 cases (20.1%) had evidence of pneumococcal disease, 172 cases were caused by the type of vaccine, and 70 cases had IPD.
Vaccine efficacy increased from 5.1% (95% confidence interval, -5%-14%) of all CAPs to 30.6% (95% confidence interval, 9.8%-46.7%) of pneumococcal CAP, and vaccine-type pneumococcal CAP 45.6% (95% confidence interval, 21.8% to 62.5%).
Subsequent analysis reports stated that during the five years of the study, the effectiveness of the vaccine differed depending on the complication status (decreased lung disease, increased diabetes), when CAP was only defined by laboratory standards (no specific radiological examination results were required), The vaccine efficacy is significant for serotype 3 and 7F, but not for serotype 1.
However, the CAPiTA study was conducted in the absence of PCV13 in infants (2008-2010), limiting the conclusions about the direct protection of PCV on the increased residual burden of PCV13 serotype disease in the elderly.
In 2014, the United States became the only country that recommended direct immunization for people over 65, even though PCV13 was funded by an insurance company in the German state of Saxony.
After the recommendation of the United States in 2014, the only published data on pneumococcal CAP came from a hospital in 2015-2016.
In this study, using the same diagnostic analysis as CAPiTA, the proportion of CAP produced by the 13v serotype was 8.1% (0.3% IPD), which was significantly lower than the 20% (4% IPD) recorded in CAPiTA and 21% (1%) in Japan. %IPD).
Among the 164 confirmed cases of pneumococcal CAP, the proportion of 13v serotype is lower than per capita or Japan, but still higher than 40% (Table 8). The effectiveness of vaccine-based CAP is estimated to be 72% (95% confidence interval) , 8.7-91.4), higher than per capita or Japan (40-46%), but the confidence intervals overlap.
Therefore, when considering the impact of PCV13 on the overall population in the United States, the relative importance of direct immunization for the elderly and indirect immunization for infants must be considered.
National surveillance through the ABCs network of the Centers for Disease Control and Prevention showed that although pneumococcal CAP was significantly reduced after PCV13 vaccination in infants, there was no significant additional reduction in pneumococcal CAP after PCV13 vaccination in adults (5%).
Is the effectiveness of the pneumococcal vaccine gender-specific?
Three studies of 23vPPV against pneumococcal pneumonia from Japan, Germany, and many countries found that the vaccine efficacy of men was significantly lower than that of women, and German studies on the efficacy of PCV13 also had similar findings.
Long-term trend of indirect effects of pneumococcal conjugate vaccine
In the United Kingdom and the Netherlands, compared with the baseline before PCV7, the IPD of people over 65 was reduced by less than 20%.
In contrast, IPD in the US has been reduced by two to three times (74%) compared to pre-PCV7, albeit at a high baseline level, while in Australia it is 32%.
However, according to the incidence rate (Table 10), after the introduction of PCV10/13, only the United States has continued to decline in IPD.
The incidence of IPD after childhood PCV10 (Netherlands) and PCV13 (Australia, United Kingdom, and the United States) with high coverage varies greatly, ranging from 51/100,000 in the Netherlands to approximately 15/100,000 in Australia and the United States, but PCV13 serotypes cause The proportion of serotypes is the lowest in the UK (19%) and is related to serotype replacement diseases.
The impact of PCV13 on American seniors and the relative cost-effectiveness of PCV13 and PPV23
The American Advisory Committee on Immunization Practice reviewed the five years of experience after recommending PCV13 and PPV23 for adults over 65 years of age in 2014, and concluded that there is no evidence that the direct use of PCV13 in the elderly leads to a reduction in the increase in vaccine-based IPD, and there is no evidence that Non-IPD CAP reduced.
A recent economic analysis found that PCV13 immunization for the elderly is not cost-effective. While the indirect reduction in IPD among the elderly is not significant, recent cost-benefit assessments conducted in the Netherlands, Australia and the UK concluded that 23vPPV rather than PCV13 meets the cost-benefit criteria, especially among adults over 70.
In Australia, PCV13 has recently been considered cost-effective for all adults over 70 years old, but it is recommended that 23vPPV be used sequentially after PCV13 only for people with severe complications and indigenous peoples.
Similar to high-dose influenza vaccines, double-dose PCV13 in people over 55 years old shows higher immunogenicity than single-dose, but has not yet proven to have higher or longer-lasting clinical efficacy.
The high-valent conjugate vaccine, 15-valent or 20-valent serotype vaccine is undergoing clinical trials and is expected to be on the market within 2-5 years.
The 20-valent vaccine includes the most prominent serotype among countries with this problem in serotype replacement.
Attempts are being made to develop a universal pneumococcal vaccine to avoid serotype replacement.
Combined vaccination of the elderly
In a study comparing pneumococcal polysaccharides and influenza vaccines, compared with influenza vaccine alone (15% reduction; 95% confidence interval, 4%-24%) or pneumococcal vaccine alone (24%; 95% confidence interval, 16 %-31%), the incidence of pneumonia was significantly reduced.
There are no studies evaluating the effectiveness of concomitant influenza and PCV, but the antibody response to certain OPA serotypes with lower serotypes suggests that the combination should be avoided when feasible.
It was initially reported that the combination of PCV13 and ZVL, the first shingles vaccine, could reduce the antibody response to ZVL, but this result has been reviewed and the US Centers for Disease Control and Prevention now recommends joint vaccination to ensure maximum To protect the elderly.
The reactogenicity, potency, or immunogenicity of RZV vaccinated with pneumococcal vaccine or influenza vaccine is similar to that of RZV vaccinated alone.
RZV is the benchmark for effective vaccines for the elderly, because it greatly reduces the risk of herpes zoster and post-herpetic neuralgia in the elderly over the age of 50, regardless of age and physical condition.
RZV will greatly reduce the social costs of herpes zoster in the elderly (including the use of antiviral drugs and painkillers and hospitalization).
RZV may also partially solve the problem of frequent and severe herpes zoster in immunocompromised patients. In countries that do not yet have RZV, ZVL is still useful in preventing or reducing shingles.
During the COVID-19 pandemic, influenza infection may have a synergistic effect similar to SARS-CoV-2 infection, so the use of enhanced influenza vaccines in autumn and winter is essential for optimal coverage of the elderly population.
Optimizing prevention of influenza and pneumococcal diseases requires more effective vaccines.
The experience gained from RZV and its development indicates that the use of one or several target antigens in combination with appropriate adjuvants may be a vaccine against other diseases of the elderly (which may include influenza, respiratory syncytial virus and COVID-19) The best choice.
Vaccines for older adults
What vaccines are recommended for the elderly?
(source:internet, reference only)
(source:internet, reference only)
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