Vaccinations

Author information

Name: Santosh Varughese and Lloyd Vincent MD, DM, FRCP (Lon)

Biography: Santosh Varughese, Professor and Head,

Department of Nephrology,

Christian Medical College,

Vellore, India.

Lloyd Vincent, Senior Consultant Nephrologist, Department of Nephrology, Narayana

Hrudayalaya Hospitals, Bengaluru, India.

<H1>Description

Learn about the management ofmanaging patients with chronic kidney disease with respect to

vaccinations.

<H1>Learning outcomes

At the end of this module, you After completing this module, you should know the following:

Why timely vaccination of patients with chronic kidney diseaseCKD is necessary

What are The the Mandatory mandatory vaccinations that every patient with chronic

kidney diseaseCKD should receive

What is The the universal vaccination schedule recommended by international bodies

<H1>Why we wrote this module?

Patients with chronic kidney disease (CKD, who have) reaching reached the point of needing

dialysis to sustain bodily functions, need to be vaccinated against the infections that they are

particularly likely to be infected with. As chronic kidney diseaseCKD is an

immunosuppressed state, patients with chronic kidney diseaseCKD have lesser immune

response to infective agents than healthy individuals. Hence, it is imperative that chronic

kidney diseaseCKD patients be vaccinated against some of these infective agents. The

timeliness of the vaccination is important, as is the dose to be administered.

<H1>Clinical tips

Patients with chronic kidney disease are particularly prone to infections as a consequence of

their immunocompromised state. They need to receive vaccinations against certain infective

agents that they are particularly prone to be exposed to. These vaccinations need to be

administered in a timely fashion, and also need to be monitored for the level of protective

antibodies in serum.

<H1>Introduction

Infections in chronic kidney disease (CKD) are a major cause of mortality. A major aspect of

infection prevention is adequate immunization. Patients with chronic kidney diseaseCKD, are

immunocompromised due to a general suppression of the immune system, due to uraemia.

The inability to mount an adequate immune response, and / or the lack of a sustained

response, predisposes these chronic kidney diseaseCKD patients to infection. The immune

defect with a diminished antibody response to vaccination is more pronounced in patients

with end -stage renal diseaseESRD on dialysis. The degree of immunocompromise is less

ascertained or documented in the early chronic kidney diseaseCKD. It is unclear if the

immune response to the vaccine correlates with the adequacy of dialysis. Generally,

increasing the dose of dialysis may lead to improved antibody titres.

Multiple causes contribute to an impaired innate and adaptive immune systems in these

patients with uraemia. The altered immune response is possibly due to disturbances in the T-

lymphocytes and antigen presenting cells, causing a suboptimal, less intense, and less durable

immune response. The antibody titers titres wane over time with an inability to maintain

protective titres. Despite the disordered immune status and impaired antibody response,

vaccinations are recommended to prevent the increased infection risk, especially in the end-

stage renal diseaseESRD populations. Specific vaccination doses, protocols, and schedules,

are designed for chronic kidney diseaseCKD with or without dialysis to elicit an adequate

immune response.

On completion of the vaccine schedules, monitoring of the antibody titres at the

predetermined periods, enables to identifying the responders. Antibody titre levels advise the

need for repeat vaccine doses in inadequate or non-responders. Those pPatients who

showconvert with an adequate antibody response with protective antibody response titres to

the infection are seroprotected. Non-responders are administered additional vaccine doses for

seroconversion and seroprotection. The focus of this reviewmodule will be to review the

vaccination strategies in chronic kidney diseaseCKD, with respect to hepatitis B virus (HBV),

tetanus, pneumococcal, influenza, varicella zoster virus (VZV), and human papilloma virus

(HPV) vaccines.

<H1>Hepatitis B vaccination

The prevalence of hepatitis B virusHBV infection is varied worldwide. Most parts of the

developing world, including middle and south Asia, have an increased prevalence of > 8%.

[1,2] Hepatitis B virusHBV with uraemia in these parts of the world, is often fatal or results

in a carrier state.  Prevention is of utmost importance, especially if an increased hepatitis B

virusHBV infection prevalence is noted. Universal precautions remain the main stay of

prevention of the spread of hepatitis B virusHBV in a haemodialysis unit. The Centers for

Disease Control and PreventionCDC recommendations suggest isolating antigen (hepatitis B

virus surface antigenhbsag)- positive patients and completely avoiding commonly used multi-

dose vials of medication (e.g., heparin) in the dialysis units. [3]

Rationale: The hepatitis B virusHBV vaccine efficacy is reduced as the antibody response is

impaired, less intense, or less durable in end- stage renal disease (ESRD).

Immunocompetence is measured by an adequate antibody response, offering disease

protection. An adequate antibody response to vaccination is seen in only 50%–-60% of the

end-stage renal diseaseESRD patients, when compared withto the response seen in more

than 90 % of patients with normal renal function. [4,5] This immune response to hepatitis B

virusHBV vaccine in chronic kidney diseaseCKD, correlates with the degree of renal failure.

In the early stage of the disease, there is a better antibody response to vaccination.

Haemodialysis patients receiving hepatitis B vaccine have a 70% percent lower risk for

infection. Controversy exists regarding the need for the vaccine in the developed world due to

the increased cost– benefit ratio, low hepatitis B virusHBV incidence (<2%), and lower

efficacy of vaccine in end-stage renal diseaseESRD patients. The high hepatitis B virusHBV

prevalence rates of > 8% in the developing world of, emphasizes the absolute need for the

hepatitis B virusHBV vaccinations of for chronic kidney diseaseCKD patients in these

regions. More rapid clinical protection is obtained with the vaccination in early chronic

kidney diseaseCKD prior to the initiation of dialysis. The use of generic vaccines with good

antibody responses, has shown to mitigate the vaccine costs. The Centers for Disease Control

and PreventionCDC recommends the vaccination against hepatitis- B virus (HBV) in all

patients with advanced chronic kidney diseaseCKD or dialysis to confer protection against

the infection.

Immunogenicity and antibody response: Multiple strategies are used to enhance the low

immune response to the hepatitis B virusHBV vaccine in end-stage renal diseaseESRD

patients. These include doubling the strength of the vaccine dose, use of booster doses with

decline in antibody titerstitres, using alternative routes of injections, e.g., intradermal route,

or the addition of adjuvants or immunostimulants. [6-–9] Two vaccines associated with

different adjuvants, namely, ASO2V and ASO4 vaccines, were studied in a randomly

assigned multicenter study. [8] The hepatitis B ASO2V vaccine provided a rapid, enhanced,

and persistent protection than that of ASO4 after three doses in chronic kidney diseaseCKD

patients. The seroconversion rates were 77% versus. 39% and 94% versus. 79% at 2 months

and 12 months, respectively.

The antibody response to vaccination are is augmented using a number of strategies,. [10-17]

including vaccine administration at diagnosis of chronic kidney diseaseCKD, in a negative

hepatitis B virusHBV antigen and antibody status. [10–17] Vaccines are administered on the

deltoid muscles to produce a better response. Doubling the dose of vaccine or an increased

numbers of doses is are administered to elicit an improved and rapid antibody response.

Dialysis patients failing to respond to the initial series of vaccinations with diminished or no

response, warrant additional doses or booster doses for an antibody response. A single

booster dose of 40 mcg administered in patients with an initial inadequate response or natural

infection is reported to improve the antibody titerstitres. No benefit is seen with additional

doses when antibody titers titres continue to remain ≤10 international units/L l with repeated

boosters.

Co-administration of other vaccines: Booster vaccinations of diphtheria, tetanus toxoid, and

pertussis can be co-administered or used singly with the hepatitis B virusHBV vaccine.

Hepatitis- A vaccine is co-administered with the hepatitis B virusHBV vaccine as a single

vaccine. No contraindications are found to in administering the hepatitis B virusHBV vaccine

in hepatitis- C positive patients. The effectiveness of the hepatitis B virusHBV vaccine is not

reduced in the presence of HIV infection. Administering standard doses of hepatitis B

virusHBV vaccine in HIV patients are is reported to maintain a 70% protection to with

hepatitis B virusHBV vaccinations at 6 months. In the absence of protection with standard

doses, additional doses are required.

Recommendations: [3] The Centers for Disease Control and PreventionCDC recommends the

vaccination against hepatitis B virus (HBV) in all patients with advanced chronic kidney

diseaseCKD or dialysis to confer protection against the infection. [3] Monitoring the antibody

response is useful to determine the need for additional vaccine doses, especially with

inadequate protection and waning antibody titerstitres. The antibody titer titre is best tested

after 4 weeks of the last dose of hepatitis B virusHBV vaccination, to avoid missing a slow

response or spurious positivity. The provision of reminders, which are preprinted or within

electronic medical records, could increase the vaccination rates in a dialysis unit.

<H1>Tetanus toxoid

Rationale: There is a little evidence focused on the immune response to tetanus toxoid in

patients with chronic kidney diseaseCKD. Antibody produced in patients with chronic kidney

diseaseCKD patients given tetanus toxoid is less than in the general population.

Evidence for vaccine induced prevention of tetanus in chronic kidney diseaseCKD patients: A

study of 66 haemodialysis patients revealed that 96.5% of the patients had protective

antibody levels (0.06 HU/ml) following the booster dose. [18] However, antibody titres

rapidly declined in 6 months, with only 62% of patients having protective levels at 6 months.

Only age impaired the immune response in these patients in the study. In another prospective

controlled trial, 55% in the non-dialysis chronic kidney diseaseCKD group and 69% in the

haemodialysis group had protective antibody after triple vaccination. All the patients in the

control group and 6 six out of the 7 seven in the post-transplant group seroconverted.

Controls responded best, while the post-transplant patients responded the least. A better

response was reported with prior hepatitis -B vaccination. [19] In another cohort of

haemodialysis patients vaccinated with tetanus toxoid, 65% and 75% were seroprotected at 1

and 5 years, respectively. The increase in the above overall protection rate at 5 years,

occurred due to more patient deaths in the initial non-responder group. [20]

Recommendations [3]: When indicated, patients with chronic kidney diseaseCKD may

benefit from the tetanus toxoid vaccination. Tetanus toxoid antibody levels need to be

checked in case of injury, as revaccination in chronic kidney diseaseCKD patients is needed

much earlier. [3]

<H1>Pneumococcal vaccination

Rationale: In patients with chronic kidney diseaseCKD, there is an increased burden of

pneumococcal disease (PD), which includes both community acquired pneumonia and

invasive disease. Pneumococcal diseasePD in chronic kidney diseaseCKD patients poses up

to a 10- fold higher mortality as compared to with that of the general population. [21, 22]

Pneumococcal vaccination in chronic kidney diseaseCKD patients evokes an immune

response of lesser intensity and duration compared to controls and the protective value needs

to be substantiated. The clinical effectiveness and protective value of these vaccines in

chronic kidney diseaseCKD lackss evidence. [23] However, an association between the

vaccine status and slightly decreased total mortality may exist in patients on dialysis. [24, 25]

Evidence for vaccine induced prevention of pneumococcal disease in end-stage renal

diseaseESRD patients: The two currently available vaccines in adults include

the pneumococcal polysaccharide vaccine (PPV23) comprising of 23 capsular polysaccharide

antigens and the pneumococcal protein -conjugate vaccine (PCV 13), where a non-toxic

protein is covalently linked to capsular polysaccharide antigens. The

pneumococcal polysaccharide vaccine PPV23 induces a humoral immune response and

protects against invasive pneumococcal disease in healthy adults. But However, evidence on

of the prevention of pneumococcal diseasePD is conflicting. The protein conjugate vaccine

PCV13 vaccination stimulates good antibody responses, produces mucosal immunity, and

prevents colonization in the healthy populations. The conjugate vaccine is preferred over the

polysaccharide vaccine due to the T-cell-dependent response of affinity, repeated exposure

causing antibody maturation, memory cell responses, and a more sustained immunity. [26]

protein conjugate vaccine PCV13 unlike pneumococcal polysaccharide vaccine PPV 23 has

revealed the above characteristics in children, and, therefore, it is the preferred vaccine when

used, in children under below 2 years of age. [27] Prior polysaccharide

pneumococcal polysaccharide vaccine PPV-23 vaccination negatively affects the subsequent

antibody response to the protein conjugate vaccine PCV-13 conjugate vaccine. The strategy,

therefore, is to administer a conjugate prime followed by a polysaccharide vaccine to enhance

the maximum serotype exposure and antibody response.

Recommendations [3]: The vaccination is found to be safe and cost- effective. Therefore,

pending clinical evidence of vaccine effectiveness, pneumococcal vaccination is advocated in

all chronic kidney diseaseCKD patients as soon as the diagnosis is made. The schedule of

recommendations of vaccination in all chronic kidney diseaseCKD patients includes the

administration of a protein conjugate vaccine PCV-13 prime vaccination followed by a

pneumococcal polysaccharide vaccine PPV-23 repeated vaccine in 8 weeks in non-vaccinated

patients. A protein conjugate vaccine PCV-13 vaccine is recommended at least 1 year after

the latest pneumococcal polysaccharide vaccine PPV-23, when a prior vaccination for

pneumococcal diseasePD has occurred. Although recommended, no evidence is supportive of

revaccination after 5 years in the chronic kidney diseaseCKD or dialysis patients. [3]

<H1>Influenza vaccination

Rationale: Pulmonary infection- related mortality is 10- fold higher in end-stage renal

diseaseESRD patients compared to that of controls. The Elderly patients with chronic kidney

diseaseCKD with or without comorbidity are at a high risk of developing influenza and its

complications. [21] From September 2010 to May 2011, the influenza- related, age -adjusted,

risk of death was 18.5% in the Britain. The mortality rate per 100,000 population in these

patients studied were was 4.8, with 5.3% being fatal. [28]

Influenza vaccination of this population may reduce the disease burden of pneumonia,

influenza, hospitalization, intensive care unitICU stay, mortality, and costs. Despite the

antibody response being lower in end-stage renal diseaseESRD patients on dialysis, there is

a four-fold increase in titers titres after vaccination, regarded as protective in 53%– to 90% of

patients, [29,30] which is unlike a the response to other vaccines, but similar to the controls.

Evidence for prevention of influenza in chronic kidney diseaseCKD patients on dialysis:

Evidence on of the protective effects of influenza vaccination in patients with end-stage renal

diseaseESRD is limited. The viral strains in the vaccine may be different from those

clinically relevant at a given moment. However, given the high rates of serious health risks of

influenza mortality in chronic kidney diseaseCKD patients, a low vaccine efficacy is

sufficient to recommend an annual influenza vaccination. The use of higher or more frequent

doses, newer recombinant vaccines, and additional protective antigens may provide a better

protection. An influenza vaccine study in on peritoneal dialysis ihas reported to lower sepsis,

hospitalization, intensive care admission, and mortality. [31]

The vaccine efficacy depends upon the T cells, B cells, and the immunoglobulin GIgG

production among patients undergoing hemodialysis. Influenza vaccines are prepared using

virus strains in line with the World Health OrganizationWHO recommendations. Most

current inactivated influenza vaccines are trivalent, containing two subtypes of influenza A

and one B virus; however, quadrivalent vaccines with an additional B virus have been

developed. Additional well-designed studies are needed, making vaccine changes to

determine the extent of influenza disease prevention.

Recommendations (3): The vaccine is advised annually prior to the onset of the influenza

season in all chronic kidney diseaseCKD patients. [3] Caregivers, household contacts, and

healthcare workers need to be vaccinated annually to reduce disease transmission.

Vaccination with H1N1 is safe and effective in the haemodialysis population.

<H1>Varicella zoster virus (VZV) vaccination

Rationale: There is a paucity of iInformation on the response to varicella zoster virusVZV

vaccine in adult end-stage renal diseaseESRD patients. Considering the suboptimal response

to other vaccines in end-stage renal diseaseESRD patients, protection offered by the herpes

zoster vaccineHZV vaccine may be suboptimal.

Evidence for prevention of varicella zoster virusVZV infection in chronic kidney diseaseCKD

patients on dialysis: One study reported the inclusion of 582 adult end-stage renal

diseaseESRD patients over above 60 years of age and evaluated the association between

herpes zoster vaccineHZV vaccination and the subsequent risk of herpes zoster vaccineHZV

infection. Each vaccinated patient in the study cohort was matched to with five unvaccinated

patients on age, sex, and dialysis duration of a control cohort. The vaccinated group

developed herpes zoster in 11.7 per 1000 person-years versus 22.3 per 1000 person-years in

the unvaccinated group suggesting that vaccination may lower the herpes zoster vaccineHZV

incidence in end-stage renal diseaseESRD patients. [32] This risk reduction seems to be

more pronounced if the vaccine is administered within two 2 years of dialysis initiation.

Recommendations (Figure-2): The varicella zoster virusVZV vaccine is recommended for

adults with end-stage renal diseaseESRD and with no contraindications such as pregnancy,

immunocompromised state, and anaphylaxis. (Figure 1). Additionally, children and adults

awaiting transplantation in whom varicella antibodies cannot be detected should probably be

vaccinated. [33, 34]

<H1>Human papilloma virus

Rationale: An increased burden of human papillomavirus (HPV) -related genital tract disease

exists in patients with chronic kidney diseaseCKD. Immune abnormalities associated with

chronic kidney diseaseCKD may prevent optimal vaccine response. Over 80% of sexually

active adults will become infected with human papillomavirus (HPV) during their lifetime.

Persistent human papilloma virusHPV infection could result in cervical, vulvovaginal, penile,

and anogenital cancers. Transplant recipients have a 10 to –100 times higher risk of human

papilloma virusHPV- associated malignancies. The prophylactic effect of the human

papilloma virusHPV vaccine is potentially profound. It is most effective when administered

before the onset of sexual activity in female and male children and in young adults.

Evidence for prevention of HPV human papilloma virus infection in chronic kidney

diseaseCKD patients: A cohort study of girls and women aged between 9– and 21 years with

chronic kidney diseaseCKD,; from pediatric nephrology clinics, were was involved in the

administration of a standard a three -dose vaccine series of the human papilloma virusHPV

vaccine. Antibody response to all the four human papilloma virusHPV genotypes studied,

namely, 6, 11, 16, and 18, was 100% in the non-dialysis chronic kidney diseaseCKD and

dialysis groups. Antibody response to the quadrivalent recombinant human papilloma

virusHPV vaccine in this study was reported to be more robust and sustained in girls and

young women with chronic kidney diseaseCKD as compared to with those in transplant

patients. [35] Another study reported that the quadrivalent human papilloma

virusHPV vaccine has been well tolerated, is safe, and provides an excellent immunogenicity

in late-stage chronic kidney diseaseCKD patients. [36] Female children and young women,

especially those anticipating kidney transplantation, should probably be offered this vaccine.

Young adult males should also probably be offered the vaccine.

Recommendations [3]: The Centers for Disease Control and PreventionCDC recommends

this vaccine for women with end-stage renal diseaseESRD through age 26 years and for men

with end-stage renal diseaseESRD through age 21 years. [3]

<H1>Summary

Patients with end- stage renal disease (ESRD) have a suppressed immune response, causing a

decreased antibody response to vaccination. Despite this suboptimal, less intense, and less

durable response, all end-stage renal diseaseESRD patients are recommended for hepatitis B

virusHBV vaccination. A number of strategies are used to augment the hepatitis B virusHBV

vaccine immunogenicity and/ or antibody response. Vaccination against hepatitis B

virusHBV infection in early chronic kidney diseaseCKD, doubling vaccine dose, using

booster doses, extended vaccine schedules, or the use of newer vaccines with adjuvants (e.g.,

ASO2V) can elicit an improved antibody response. The Chronic kidney diseaseCKD patients

also have a diminished antibody response to pneumococcal vaccine, especially in the

maintenance of adequate titerstitres. There is limited evidence, suggesting that H1N1 vaccine

is safe and effective in end-stage renal diseaseESRD patients. Due to the lack of durability

of the antibody, all these patients should also receive an influenza vaccine annually. There is

a lack of evidence on the vaccinations for human papilloma virus (HPV) and varicella zoster

virus (VZV). However, these vaccines should be considered, more so, in patients awaiting

kidney transplantation.

QuestionsTest Ms. S is a 28-year-old lady with reflux nephropathy and chronic kidney disease. Her recent

laboratory results show an elevated serum creatinine and an estimated glomerular filtration

rate (eGFR) of 47 ml/min/1.73 m2.

[1.] At which time point is it mandatory that we vaccinate her against hepatitis B virus?

A) At the earliest

B) After a year

[C)] When the estimated glomerular filtration rateeGFR drops to < 20 ml/min/1.73 m2

[D)] When the estimated glomerular filtration rateeGFR drops to < 30 ml/min/1.73 m2

[correct answer]

[E)] When she develops symptoms of end- stage renal disease

Correct Answer: D

Explanation - Question 1

Correct answer is d

When the eGFR drops to < 30ml/min/1.73m2 [correct answer]

Patients with chronic kidney disease must receive vaccination against hepatitis B

virus when the estimated glomerular filtration rateeGFR drops below 30 ml/min/1.73

m2

Question 2

[2.] The hepatitis B virusHBV vaccination schedule that we should use could involve

which of the following?

A) No change from the general population

[B)] Doubling the strength of the vaccine dose administered in chronic kidney

diseaseCKD patients

B)[C)] Annual boosters irrespective of titres achieved

[D)] An additional dose when the the estimated glomerular filtration rateeGFR drops

to < 10 ml/min/1.73 m2

C)[E)] Vaccination is avoided in those positive for hepatitis C virus serology

Correct Answer: B

Explanation: Doubling the strength of the vaccine dose administered in CKD patients

Patients with chronic kidney disease may not mount an adequate immune response and

strategies like such as vaccinating early in the course of chronic kidney diseaseCKD,

doubling the dose of vaccine, using booster doses, using an extended vaccine schedule, and

the use of newer vaccines with adjuvants (e.g., ASO2V) may be used to augment the hepatitis

B virusHBV vaccine immunogenicity and antibody response.

Question 3

[3.] Why is timely vaccination of every patient with chronic kidney diseaseCKD

necessary?

[A)] Patients with chronic kidney diseaseCKD are immunosuppressed and are particularly

prone to infections, so they need to be vaccinated early and monitored regarding the

adequacy of the antibody titres.

[B)] Patients with chronic kidney diseaseCKD are often elderly, and their immune

response is poor.

[C)] Patients with chronic kidney diseaseCKD may have missed receiving their childhood

vaccines.

[D)] Patients with chronic kidney diseaseCKD have herd immunity, which may wax and

wane.

[E)] Patients with chronic kidney diseaseCKD are more prone for to infections than

transplant recipients.

Correct Answer: A

Patients with CKD are immunosuppressed and are particularly prone to infections so

they need to be vaccinated early and monitored regarding adequacy of the antibody

titres. [correct answer]

Patients with chronic kidney disease are particularly prone to infections as a

consequence of their immunocompromised state. They need to receive vaccinations

against certain infective agents that they are particularly prone to be exposed to. These

need to be administered in a timely fashion and also need to be monitored for the level

of protective antibodies in serum.

Question 4

[4.] What are the mandatory vaccinations that every patient with chronic kidney

diseaseCKD should receive?

[A)] Vaccination against hepatitis B virusHBV, hepatitis C virus, and pneumococci

A)[B)] Vaccination against hepatitis C virus, influenza virus, and pneumococci

B)[C)] Vaccination against hepatitis B virus, hepatitis C virus, and cytomegalovirus

C)[D)] Vaccination against pneumococci, hepatitis B virus, and influenza virus

D)[E)] Vaccination against pneumococci, hepatitis B virus, and cytomegalovirus

Correct Answer Answer: D. Vaccination against Pneumococci, Hepatitis B virus and

Influenza virus

In general, while vaccination against all possible infections is preferred, vaccinations

against hepatitis B virus, influenza virus, and pneumococci are presently considered

mandatory for all chronic kidney diseaseCKD patients. However, vaccinations against

hepatitis C virus and cytomegalovirus are as yet not available.

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