JOURNAL READING

Non-Responder
Covid-19 Vaccine
VACCINE FAILURE
VACCINE FAILURE

Incomplete attenuation

Vaccine
Incorrect route or schedule
Related
Failures to delivery interruption
VACCINE of the cold chain
FAILURE
Immune and health status

Host
Age
Related

Genetics

Wiedermann U, 2016. Primary Vaccine Failure to Routine Vaccines : Why and What to do?.
PRIMARY VACCINE FAILURE

▪ Non-responsiveness or primary vaccine failure currently described by

the inability of the host/vaccinee to mount sufficient protective
antibody responses after primary or booster vaccination.
▪ This phenomenon affects about 2–10% of vaccinated healthy
individuals, but the immunological background, the clinical
consequences, or the question of whether vaccine failure is antigen-
specific or a general phenomenon are largely unknown.

Wiedermann U, 2016. Primary Vaccine Failure to Routine Vaccines : Why and What to do?.
PRIMARY VACCINE FAILURE

▪ The most documented is non-responsiveness to hepatitis B vaccine in

which up to 10% of otherwise immunocompetent persons do not respond
with protective antibody levels to the hepatitis B surface antigen in the
vaccine.
▪ Risk factor such as obesity, heavy smoking or chronic renal failure have
been described in addition to genetic predisposition in certain HLA class
II haplotype (HLA-DRB1, HLADQB1).

Wiedermann U, 2016. Primary Vaccine Failure to Routine Vaccines : Why and What to do?.
PRIMARY VACCINE FAILURE

▪ Genetic predisposition to vaccine failure has also been described for

other vaccines such as influenza.
▪ Significant number of non-responders in hepatitis A vaccinees in an
unselected patient collective of travelers → 2% were characterized by a
lack of specific antibodies after primary vaccination.
▪ Also in individuals vaccinated against tick-borne encephalitis → a non-
responder rate of about 5%.

Wiedermann U, 2016. Primary Vaccine Failure to Routine Vaccines : Why and What to do?.
MECHANISM OF VACCINE
FAILURE
VACCINE FAILURE

Immuno-
competent
Less
immunogenic
Immuno- ↓ in the B- and T
Vaccine Increased senescence cell repertoire
Failure Age
Less effective
Altered
Atopic responsiveness to
routine vaccines
Risk
Population
low-grade Immuno-
Obese
inflammation suppression
Wiedermann U, 2016. Primary Vaccine Failure to Routine Vaccines : Why and What to do?.
HBV-VACCINE VACCINE
FAILURE
HEPATITIS B VACCINE

▪ In children, the HBV vaccine is normally administered intramuscularly

(IM) at birth and 2, and 6 months of age, while adults requiring
vaccination receive a three dose series at monthly intervals.
▪ The HBV vaccine consists of recombinant hepatitis B surface antigen
(HBsAg), an aluminum hydroxide (alum) adjuvant, and a virus-like
particle.
▪ The alum adjuvant induces humoral immunity by promoting
production of HBV envelope-specific antibody (anti-HBsAg) through T-
helper (Th2) cell stimulation and production of IL-4.

Saco TV, et al. 2018. Hepatitis B vaccine non-responders: possible mechanisms and solutions
HEPATITIS B VACCINE

▪ However, alum does not augment T-cell responses as effectively as other

adjuvants, thus newer more immunogenic adjuvants are currently being
researched.
▪ Anti-HBsAg titers are used to assess the adequacy of the humoraL
immune response to the HBV vaccine.

Saco TV, et al. 2018. Hepatitis B vaccine non-responders: possible mechanisms and solutions
IMPAIRED HEPATITIS B VACCINE IMMUNE RESPONDERS

▪ A response to the HBV vaccine is defined as the production of an anti-

HBsAg level ≥10 IU/L with >100 IU/L accepted as a protective titer.
▪ If confirmation of immune response is necessary, the titer is checked 1 to
2 months after completing a vaccination series.
▪ CDC does not recommend routine post-vaccination titers except for
infants born to mothers with HBV, immunocompromised individuals,
healthcare workers and sex partners of persons with chronic HBV.

Saco TV, et al. 2018. Hepatitis B vaccine non-responders: possible mechanisms and solutions
IMPAIRED HEPATITIS B VACCINE IMMUNE RESPONDERS

▪ HBV non-responders or hyporesponders are subjects who fail to

produce an anti-HBsAg titer ≥ 10 IU/L or between 10 – 99 IU/L, after
undergoing two HBV vaccine series of 3 immunizations.
▪ 5-10 percent of immunocompetent subjects meet non-responder criteria.
▪ Vulnerable populations include subjects with HIV, HCV, ESRD
receiving dialysis, diabetes, obesity, celiac disease and IBD, some elderly
subjects and those with certain genetic risk factors.

Saco TV, et al. 2018. Hepatitis B vaccine non-responders: possible mechanisms and solutions
Susceptible
Potential Mechanism Results
Populations
HIV ↓ CD4+ cells Alternated CD8+ Supress protection against HBV replication
activation
↓ CD40L ↓ Ig Isotype switching

HIV viremia Constitutive innate Attenuates T-cell dependent adaptive

immune activation immune actions and induces immune
senescence

High viral loads B-cell dysfunction unrelated to impaired

activation via CD4+ cells
Induces cytotoxic destruction of gp120 CD4 +
T-cells and CD4+ cell apoptosis

HCV ↑ Inhibitory PD-1 ↑ PDL-1 binding ↓ T-cell stimulation

receptors on T-cells and
B-cells

↑ KLRG1 on NK and T- ↓ T-cell proliferation CD4+ dysfunction

cell
↓ IL-2

↑ cell cycle inhibitors

Saco TV, et al. 2018. Hepatitis B vaccine non-responders: possible mechanisms and solutions
Susceptible
Potential Mechanism Results
Populations
HCV ↑ Tim-3 (T-cell fatigue ↓ IL-12 ↑ IL-23 ↑ differentiation of CD4+ to Th17
marker) on
monocytes
Induced production of dysfunction Igs by B-
cells (can’t recognize HBsAg)
ESRD and Uremia ↓ T-cell production Impaired adaptive immunity
Dialysis ↓d MHC II on
monocytes
↓ TCR expression
Imbalance of adhesion molecules (↓ ICAM-1, ↑ Impaired T-cell response
LFA-1)

↓ phosphorylation of ITAMS ↓ T-cell proliferation

↓ CD86 on APCs ↓ binding of APC T-cell apoptosis/anergy

CD80/CD36 to T-cell
CD28
Premature activation of Excessively high Monocytes senescence and apoptosis in
monocytes levels of IL-1β, IL-6, vitro
IL-12

Saco TV, et al. 2018. Hepatitis B vaccine non-responders: possible mechanisms and solutions
Susceptible
Potential Mechanism Results
Populations
ESRD and Cellulose dialysis Alternative C5a Premature monocyte activation
Dialysis membranes complement upregulation
pathway
stimulation
Prematuse actvation ↑ TNF-α secretion Early apoptosis of T- and B-cells
of T- and B-cells

Low-flux polysulfune Medium molecular weight ↑ T-cell apoptosis

dialysis uremic toxins are not removed

Compromised T-cell production

Iron overload from frequent blood transfusions

Diabetes Type I Diabetes ↓ T-cell response

↓ MHC II
Mellitus
Obesity ↓ splenic CD4+ T-cells Impaired cell mediated immunity
↓ T-cell activation
↓ DC with CD83/CD86
Increased IL-10
Celiac Disease Gliadin saturation of Prevents binding of vaccine
↓ anti-HBsAg titers
& IBD HLA-DQ2 HBsAg
IBD HLA, IL-10, IL-23 ↓ adaptive immunity

Saco TV, et al. 2018. Hepatitis B vaccine non-responders: possible mechanisms and solutions
 Susceptible
Potential Mechanism Results
Populations
Celiac Disease IBD therapy
& IBD (corticosteroids and ↓ TNF-α and IFN- γ Impaired T-cell activation
TNF-α inhibitors)

Hypoalbuminemia Impaired T-cell maturation and interaction

with HBsAg
Advanced age Reduction of thymic size with age ↓T-cell production and impairs
(Immune differentiation to CD4+ T-cells, CD8+ T-
senescence) cells, and memory T-cells
Progressive loss of CD28 molecules on T-cells
T-cell anergy and apoptosis

↓ CD4+ T-cells impairs germinal center activation, which

results in attenuated antibody production
loss of CD86 on B-cells Inhibition of co-stimulation of B-cells and
antibody production
↓ adhesion molecule CD62L ↓ migration of undifferentiated T-cells and
memory T-cells into lymph nodes
Impairs T-cell activation of B-cells and
subsequent antibody formation

Saco TV, et al. 2018. Hepatitis B vaccine non-responders: possible mechanisms and solutions
Susceptible
Potential Mechanism Results
Populations
Genetics
HLA-DRB1
HBV vaccine non-responsiveness
SNP rs477515

HLA-DRB1 SNP rs28366298

HLA-DRB1 SNP rs3763316

Enhanced HBV vaccine response
HLA-DRB1 SNP rs13204672

HLA-DRB1 SNP rs7770370

Absence of HLA-A*02

Absence of HLA-DB1*08 HBV vaccine non-responders

Presence of HLA-B*15

Saco TV, et al. 2018. Hepatitis B vaccine non-responders: possible mechanisms and solutions
HOW ABOUT COVID-
19 VACCINE?
RESPONSE IN AN IMMUNIZED PERSON

▪ When adaptive immune cells (B

cells and T cells) encounter the
same virus again, they respond
rapidly and the immune system can
effectively clear an infection before it
causes disease
▪ Vaccines use this immune memory
to protect us from infection
▪ Immune memory can result from a
prior infection or from an effective
vaccine

WHO. 2020. Update on COVID-19 vaccines & immune response.

RESPONSE IN AN IMMUNIZED PERSON
▪ Vaccines safely deliver an
immunogen (antigen able to elicit an
immune response) to the immune
system in order to train it to recognize
the pathogen when it is encountered
naturally by activating:
▪ CD4+ helper T cells that in turn
stimulate:
▫ B-cells to produce neutralizing
antibodies specific to the virus
▫ CD8+ cytotoxic T cells to
recognize and kill cells infected by
the virus

WHO. 2020. Update on COVID-19 vaccines & immune response.

IMMUNOGENS USED IN COVID-19 VACCINES

▪ An immunogen is a specific type of antigen that is able to elicit an immune

response
▪ The choice of immunogen for vaccines impacts what type of immune response is
induced; as well as safety, development time, production time, costs and access
to vaccines
▪ Immunogens used in current COVID-19 vaccines or COVID-19 vaccines in
development:

Inactivated
Viral Subunit Viral Vector RNA vaccines
Virus

WHO. 2020. Update on COVID-19 vaccines & immune response.

IMMUNOGENS USED IN COVID-19 VACCINES
EXAMPLE
IMMUNOGEN WHAT IT IS ADVANTAGE DISADVANTAGE OF
VACCINES
Requires large quantities of Influenza,
Induces strong antibody
Inactivated virus Inactivated dead virus
response
virus, low or no cellular rabies
response hepatitis A
May have fewer side
A protein derived from effects than whole virus May be poorly immunogenic;
Viral subunit a pathogen (redness, swelling at complex process
Influenza
injection site)

Prior exposure to vector

Viral pathogen virus (eg. adenovirus) may
Rapid development,
expressed on a safe reduce
Viral vector virus that doesn’t
strong cellular response,
immunogenicity, some
Ebola
relatively easy to produce
cause disease vectors require boosting with
a different vector

mRNA coding for a viral Strong cellular immunity; Relatively low antibody
Nucleic acid protein rapid development response
COVID-19

WHO. 2020. Update on COVID-19 vaccines & immune response.

INACTIVATED VIRUS VACCINE
▪ In inactivated virus vaccines, the genetic
material of the virus has been destroyed
to stop disease producing capacity.
▪ Inactivated virus cannot replicate inside the
body, so higher doses are needed.
▪ Sometimes, an adjuvant (molecules that
stimulate the immune system) is used to
help strengthen the immune response.
▪ Inactivated virus vaccines generally only
induce antibody-mediated immunity (not
cell-mediated immunity).

WHO. 2020. Update on COVID-19 vaccines & immune response.

VIRAL SUBUNIT VACCINE
▪ Subunit vaccines use the antigen of the virus
without any genetic material, usually with an
adjuvant to give a better immune response.
▪ Usually made using recombinant expression
system (made in a cell without using the virus).
▪ With the help of antigen-presenting cells, the
antigens are recognised by T helper cells as
with a real viral infection.
▪ Subunit vaccines generally induce mainly
antibody-mediated immunity.
▪ adjuvants can enhance antibody response and
also cell-mediated immunity.

WHO. 2020. Update on COVID-19 vaccines & immune response.

VIRAL VECTOR VACCINE
▪ Viral vector vaccines use a noncoronavirus
vector modified to include a gene that
encodes a target antigen. Examples:
adenovirus, measles virus, vesicular stomatitis
virus.
▪ Can be replicating or non-replicating. Non-
replicating: infects a cell and produces SARS-
CoV-2 antigen in that cell but not new virus.
Replicating: upon infection produces SARS-
CoV-2 antigen in that cell and new virus which
infects other cells.
▪ The SARS-CoV-2 antigen inside cells seen by
body as if SARS-CoV-2 infection and induces T
helper cells and cytotoxic T cells.

WHO. 2020. Update on COVID-19 vaccines & immune response.

m-RNA VACCINE
▪ RNA vaccines are antigen-coding strands of
messenger RNA (mRNA) delivered inside a
lipid coat.
▪ Once inside cells, the mRNA is translated the
protein antigen.
▪ The antigen is recognised, inducing an
immune reaction.
▪ Seen by body as if virus inside cell so induces
T-helper and cytotoxic T-cells, and antibodies.
▪ mRNA also recognised by cells as ‘pathogen’
stimulating strong immune response.

WHO. 2020. Update on COVID-19 vaccines & immune response.

LOWER COVID-19 VACCINE IMMUNE
RESPONSE
▪ There are no definition yet on non-reponders.
▪ Demographical and clinical factors associated with a lower COVID-19
vaccine immune response are:
▫ Male sex
▫ Older age (i.e., > 65 years)
▫ High body mass index (i.e., ≥ 25 kg/m2)
▫ Immunosuppressive treatments
▫ Cancer (especially hematologic malignancies)
▫ End-stage renal disease/dialysis
▫ Endemic appearance of novel variants of concern (VOCs)

WHO. 2020. Update on COVID-19 vaccines & immune response.

SEROLOGICAL ASSESSMENT

▪ The current evidence suggest that the initial time points may entail a
baseline assessment followed by serial measurements at 1 and 6 months
after the last vaccine dose.
▪ The 1-month measurement → timely identification of low- or non-
responders.
▪ The 6-month measurement → antibody decay rate.
▪ In both cases, consideration could then be made for strengthening
preventive measures or even administering vaccine boosters.

Lippi G, et.al. 2021. SARS-CoV-2 Antibodies Testing in Recipients of COVID-19 Vaccination : Why, When, and How?
SEROLOGICAL ASSESSMENT

▪ Additional time points for drawing blood and anti-SARS-CoV-2 serological

testing will then be defined as evidence on the kinetics of the humoral (and
cellular) immune response accumulates over the coming months.
▪ There is now solid evidence that the neutralization activity of post-infection or
post-vaccination serum mostly resides in the presence of antibodies targeting
the SARS-CoV-2 spike protein and or its RBD.
▪ The selected immunoassay shall be preferably based on detection of
antibodies targeting the SARS-CoV-2 trimeric spike glycoprotein
conformation, its S1(/S2) subunit, and its RBD, since these will reflect the
greatest burden of neutralizing potential.

Lippi G, et.al. 2021. SARS-CoV-2 Antibodies Testing in Recipients of COVID-19 Vaccination : Why, When, and How?
SEROLOGICAL ASSESSMENT

Advantages Drawbacks
▪ Assessment of baseline seroprevalence ▪ No equivalence to date between anti-
of SARS-CoV-2 infection in non- SARS-CoV-2 antibody titer and vaccine
vaccinated individuals efficiency
▪ Identification of low- or non-responders ▪ No perfect equivalence between anti-
to COVID-19 vaccinations SARS-CoV-2 antibody titer and
▪ Timely detection of the fast decay of neutralizing activity
anti-SARS-CoV-2 antibody levels ▪ Cost-effectiveness of different testing
strategies needs to be proven
▪ Enormous volume of blood drawings
and increase of laboratory workload
Lippi G, et.al. 2021. SARS-CoV-2 Antibodies Testing in Recipients of COVID-19 Vaccination : Why, When, and How?
 ▪ Therefore, although cases of SARS-CoV-2 re-infection due to waiving of
humoral immunity, VOCs, or both are increasingly reported, more
research is urgently needed to define:
▫ The individual protective threshold level of anti-SARS-CoV-2 antibodies below
which the humoral defense against different SARS-CoV-2 variants is more likely
to fail
▫ Whether the memory B cells primed by previous SARS-CoV-2 infection or
COVID- 19 vaccination can be rapidly reactivated and will be capable of
generating an efficient anti-SARS-CoV-2 antibody level
▫ The role of cell-mediated immunity in protecting from SARS-CoV-2 infection and
especially in averting the risk of developing severe or critical forms of the disease.

Lippi G, et.al. 2021. SARS-CoV-2 Antibodies Testing in Recipients of COVID-19 Vaccination : Why, When, and How?
“
WE ARE IN THIS TOGETHER –
AND WE WILL GET THROUGH
THIS, TOGETHER.

Antonio Guterres Secretary-General of the United Nations

THANK
YOU