Infectious Diseases and Vaccines

1. Radinal Kautsar (24/538537/PBI/02028)

2. Rizky Nur Endah Sari (24/547140/PBI/02043)
3. Salsabila Faradisa Nuris (24/533166/PBI/02012)
4. Tri Susiloningsih (24/548064/PBI/02059)
5. Zahrotin Saleha (24/546181/PBI/02038)
 Sub Themes

Bacterial Parasitic Infections

Influenza Virus
Tuberculosis (TB) (Helminths)

Fungal Infection Vaccines

Tuberculosis Bacteria (TB)

Caused by Mycobacterium Most commonly affect the lungs

tuberculosis bacterial infection function
Tuberculosis Bacteria (TB)
Case Overview of TB
infections

Source: Alsayed &

Gunosewoyo, 2023
Tuberculosis Bacteria (TB)
Immunopathogenesis of TB
Source:
Riensya, 2019
Tuberculosis Bacteria (TB)
Innate Immune
Response against TB
infection

Source:
Riensya, 2019
Tuberculosis Bacteria (TB)
PAMPs Structure of M.
tuberculosis bacteria

Source:
Riensya, 2019
Tuberculosis Bacteria (TB)
PRRs Structure on
the APC Membrane

Source:
Riensya, 2019
Tuberculosis Bacteria (TB)
APC Interaction with Naive
T Cell

Source: Reinsya, 2019

Tuberculosis Bacteria (TB)
Adaptive Immune
Response against TB
Infection

Source:
Reinsya, 2019
 Vaccine Development of Tuberculosis Bacteria (TB)
• BCG
The only licensed vaccine used to prevent TB.
• Vaccine candidate including an adjuvant or protein M72/AS01E
Recombinant vaccine that was developed to improve the
immune response elicited by BCG.
• TB vaccine candidate containing intact or extracted
mycobacterial cells M. vaccae
Made from M. vaccae, a nonpathogenic species typically found
in soil
 Vaccine Development of Tuberculosis Bacteria (TB)
• An attenuated M. tuberculosis vaccine candidate MTBVAC
Made from two separate, stable deletion in the phoP and fadD26
genes
• Recombinant candidate vaccine TB VPM1002
Recombinant strain of BCG vaccine that generates
membrane-penetrating listeriolysin.
 Challenges in Vaccine Development of TB
• Unsustainability of TB vaccine clinical trials
• The selection of suitable immunogenic antigenic epitopes
• Clinical trials on TB vaccines for pregnant women is lacking
• Controversies in the evaluation of endpoints of TB vaccine
clinical trials
Influenza Virus

Influenza virus that consist of four virus types:

Alphainfluenzavirus (IAV), Betainfluenzavirus (IBV),
Gamma-influenzavirus (ICV), and Deltinfluenzavirus (IDV)

Contain a negative sense single-stranded, segmented RNA with

total of eight RNA segments that encode for RNA polymerase
subunits (PB1, PB2, PA), viral glycoproteins hemagglutinin and
neuraminidase (HA, NA), viral nucleoprotein (NP), matrix
protein (M1), membrane protein (M2) and the non-structural
protein (NS1)

IAV and IBV currently could circulate in humans causing

seasonal epidemics and occasional pandemics while, ICV only
Mtambo, et al., 2021;
Skelton and Huber,
2022
causes mild illness and IDV is incapable of human infection
 Influenza Virus

In human, influenza virus infect cells of the upper respiratory

tract (URT) epithelium transmitted from an infected person
predominantly by aerosol or droplet, but more severe
infection also could infect lower respiratory tract (LRT).

Typical symptoms include sudden onset of fever, muscle

pain, headaches and exhaustion, peaking 2–3 days after
infection and resolving within 1–2 weeks.

Seasonal influenza vaccines are available but must be

regularly updated because mutational change of these
viruses by antigenic shift and antigenic drift, lead to
Francis, et al., 2019; Mifsud, et al., 2021
antigenically divergent viruses that may no longer be fully
recognized by the immune system.
Influenza Virus

Death: 1 in 30 of the global

population in 18 months

Francis, et al., 2019

Yearly, influenza viruses infect between 5% and 15% of the population with higher incidences (~30%) in
children. With at-risk groups include infants, older adults, pregnant women, and the immunocompromised.
Influenza Virus

Hutchinson, E. C. 2018
 Innate Immune Responses to the Influenza Virus
Mucous Layer as Barrier
Mucin acts as a barrier to the influenza virus by having their sialic
acids α-2,6 bind with HA of influenza virus and trap them in
mucous layer. Virus’ NA is important to avoid mucous layer
traping.

Soluble Proteins against Influenza Virus Infection

Surface protein, SP-A occupies the HA binding site in epithelial
cell (the sialic acid) while SP-D neutralises the influenza virus
through interaction with high mannose oligosaccharides near the
HA binding site.

α-defensins induce viral aggregation and promote neutrophil

uptake of them; and also binding to epithelial cells to inhibit
protein kinase C (PKC) activation that essential in RNP assembly.
Secretion of β-defensins constitutively also act as
Mifsud, et al., 2021 immunomodulatory to less the viral burden.
 Innate Immune Responses to the Influenza Virus
PAMPs Related Responses to Influenza Virus
1. TLR-3 induce TRIF activation and recognize
double-stranded RNA replication that would
activate RNA helicases. While TLR-7/8 recognize
single-stranded RNA so it induce MYD88.
2. RIG-I also would associates with shorter viral RNA
molecules or sub-genomic defective interfering
particles to induce mitochondrial antiviral
signaling protein (MAVS).
Both of these signaling induce pro-forms of IL-1β, IL-18
and Caspase-1 production
3. Activation of NLRP3 by either recognition of viral
RNA, M2 protein or PB1-F2 would also activate
inflammasome that cleavage caspase-1 then
cleaves the pro-forms of IL-1β and IL-18. These
would induce proinflammatory form of cell death
known as pyroptosis, further limiting viral
Mifsud, et al., 2021
propagation, and dissemination
 Innate Immune Responses to the Influenza Virus
Interferon Stimulated Genes in Influenza Virus Suppression
Type I and III interferon (IFN) induce the expression of hundreds of
genes, grouped as IFN-stimulated genes (ISGs). ISGs-derived proteins
limit viral replication by shutting down protein synthesis and triggering
apoptosis. They also activate key components of the innate and adaptive
immune systems, including antigen presentation and production of
cytokines for T and B cell activation. Some of the key genes are:

1. Myxovirus resistance protein (Mx) inhibit viral nucleocapsid entry

into the nucleus
2. IFN-induced transmembrane protein 3 (IFITM3) blocks
pH-dependent fusion during late endosomal entry.
3. Interferon regulatory factor 7 (IRF7) is the master regulator of
type I IFNs, mutation of this gene lead to the failed generation of
an IFN response.

Klein et al. (2023)

 Innate Immune Responses to the Influenza Virus

Macrophages, Monocytes and Dendritic Cells during

Influenza Virus Infection

1. Macrophages are abundant in the LRT but are less

in URT so they would only play a pivotal role in
eliminating the virus and trigger wound repair in
LRT.
2. Monocytes are rapidly infiltrate the URT following
influenza virus infection and when infected produce
chemokines and cytokines such as MCP-1, IL-6 and
IL-8
3. NK killer cells do viral clearance by recognizing and
lysing influenza virus-infected cells
4. Dendritic cells (DCs) that are professional antigen
presenting cells in the URT are CD103+ DCs. Once
activated they move to lymph nodes and cross
present antigens to CD8+ T cell.
Russell, M., 2024. BioRender.
 Adaptive Immune Responses to the Influenza Virus

Antibodies raised by an initial encounter

cannot neutralize the newly encountered
viruses, but T cells still recognizing the
epitopes of viral proteins that are
conserved, usually ‘internal’ viral proteins,
resulting in infected cells presenting viral
peptides on MHC-II.

CD4 T cells and CD8 T cells could still

contribute to heterosubtypic immunity
after recognizing the viral antigens and
release diverse soluble factors

Finn & McKinstry, 2024

 Adaptive Immune Responses to the Influenza Virus

As virus, like IAVs mutate frequently to

escape host immunity, long-lived humoral
immunity generated by first exposure is
limited to a given IAV strain and closely
related strain

MBCs that were generated during a

childhood response to IAVs to respond to
subsequent IAVs exposures, a phenomenon
known as original antigenic sin (OAS),
imprinting, and antigenic seniority.

Recalled MBCs can either rapidly differentiate

into PBs or re-enter into GCs to further affinity
Guthmiller, 2021
mature against the inducing strain
Adaptive Immune Responses to the Influenza Virus

People imprinted with a particular subtype are

less susceptible to seasonal IAV infections
with the same subtype later in their life, such
as 1918 and 1957 H1N1 elder people would
likely not infected by 2009 pH1N1.

But, MBCs from childhood exposures may

also negatively impact humoral immunity
against a drifted variant of the same
subtype.

Furthermore, pre-existing circulating

antibodies may mask virus antigens and
hide them from B cell receptors, thereby
inhibiting B cell activation
Seasonal Vaccine Development
Seasonal influenza, also known as interpandemic influenza, is caused by IAV and IBV each year
and due their rapid mutation, seasonal vaccines also have been developed each year.

Krammer, 2019
Seasonal Vaccine Development

The formulation of influenza virus

vaccines is re‑assessed twice
annually (in February in the Northern
Hemisphere and in September in the
Southern Hemisphere). Researchers
analyse genetic sequence data and
phylogenetic branching patterns to
predict which virus lineages are likely
to survive or to become extinct.
This method is combined with tools
that track the real-time evolution of
influenza viruses, like NextFlu.

Petrova and Russell, 2018

 Emerging Infection Impact on Global Health
The seasonal nature and short duration,
combined with the large viral diversity make the
newly emerged variants, even when they are
more fit, have little time to compete to replicate
to high levels and to become subsequent
epidemics

The majority of influenza virus infections in

temperate regions occurring in the winter
months and in tropical regions during the rainy
season.

Increasement in time spent indoors, host mixing

in confined spaces and additionally, seasonal
fluctuations in human immunity, particularly
during the winter months in which pro-
inflammatory responses are upregulated may
Petrova and Russell, 2018
have role in the transmission.
 Emerging Infection Impact on Global Health

Petrova and Russell, 2018

● Back and forth migration may spread seeding of epidemics in temperate regions from and to the
tropics
● The global circulation pattern of seasonal influenza show vary rate of antigenic evolution of
different virus types and subtypes, A/H1N1 and influenza B viruses sporadically persist locally while
A/H3N2 viruses that spread globally from E–SE Asia. Likely a result of differences in the rates of virus
evolution
Parasitic Infections (Helminths)

Helminths are a group of worms

with morphologically similar body
structures. Most species are
parasitic and typically reside in the
digestive tract of their hosts, where
they derive nutrients for survival.

Helminths have infected over 1

billion people worldwide.
Impacts: Malnutrition, organ damage, immunosuppression
Nematodes (Roundworms)

- Vary in size: MICROSCOPIC to MACROSCOPIC

- NOT all are parasitic
can be PLANT or ANIMAL-SPECIFIC
Intestinal-Related Nematodes

Reside in the digestive system.

Example:
- Ascaris lumbricoides
- Enterobius vermicularis
- Trichuris trichiura

A parasite that, by current

estimates, is harbored by
more than 800 million people
worldwide
Life Cycle of A. lumbricoides
Tissue-Related Nematodes

- Toxocara canis
- Onchocerca volvulus
- Wuchereria bancrofti

Life Cycle of
Toxocara canis
 Aspect Intestinal-related nematodes Tissue-related nematodes

Primary Infection Site In the gastrointestinal tract In body tissues like muscles,
(intestines) blood, lymph, or other organs

Mode of Transmission Through consumption of Through insect bites, skin contact,

contaminated food/drinks with or consumption of infected larvae
eggs or larvae

Life Cycle Usually simple, involves a More complex, often involves a

single host vector or intermediate host

Common Symptoms Digestive issues like diarrhea, Localized or systemic

abdominal pain, anemia, inflammation, swelling, fever,
malnutrition muscle pain, or organ dysfunction
Cestodes (Tapeworms) Trematodes (Flukes)
Flat, ribbon-like body; no digestive Leaf-shaped body; complex life cycle
system. involving snails as intermediate hosts.
Absorbs nutrients directly from the
host. Examples:
● Schistosoma mansoni (blood fluke):
Examples:
Lives in blood vessels, causing
• Taenia saginata (beef tapeworm):
granuloma and fibrosis around eggs.
Resides in the intestine.
● Fasciola hepatica (liver fluke):
• Echinococcus granulosus (hydatid
Migrates to bile ducts, causing liver
disease): Larvae form cysts in
damage and chronic inflammation.
organs like the liver and lungs.
Immunomodulation by Helminth Infections
Excretory/Secretory (ES) products are the main immunomodulatory molecules used by helminths.
They play a key role in:
- Avoiding harmful immune responses.
- Regulating the host immune system to
create a favorable environment for parasite
survival
Ex: TGF-β mimics from Fasciola hepatica
(A) Helminths influence Treg cells and TGF-β
signaling, driving immune modulation.
(B) The systemic effects of helminth infections
include influencing allergies, autoimmunity,
vaccine efficacy, and cancer immunity, often
(Maizels & McSorley, 2016)
studied in mouse models.
Immune responses to Helminths

(Gazzinelli-Guimaraes & Nutman, 2018)

Acute Phase:
● Helminths activate Th2 responses.
● Cytokines involved: IL-4, IL-5, IL-13 → drive eosinophil and IgE
production.
● Mucus production increases to expel larvae.
Chronic Phase:
● Regulatory T cells (Tregs) dominate.
● IL-10 and TGF-β suppress inflammation.
● Shift to tolerance → protects tissue but may limit vaccine efficacy.
Approaches to Developing Vaccines
Against Parasitic Infections
Example:
Na-GST-1 from Necator
americanus (hookworm)

Vaccines targeting cercariae

(Schistosoma larval stage) to
prevent adult development

Schistosoma mansoni targeting

Sm28GST (cysteine protease)

Na-GST-1 hookworm vaccine

paired with albendazole
 Fungal Infection ~ Candida Albicans
Candida albicans is a comensal fungus found in the digestive
tract and on other mucosal surfaces of the body (e.g. oral
cavity, gastrointestinal, and vagina)

Commensal sites of C. albicans (d’Enfert et al., 2021)

Adaptive immunity against C. albicans in health and disease (Swidergall & LeibundGut, 2022)
(Invasi C. albicans
(Basmaciyan et al., 2019)

(Richardson et al., 2018)

(d’Enfert et al., 2021)
Source images: Kaur et al., 2023
Basics of vaccine immunology

Source:
https://www.who.int/news-room/feature-stories/detail/how-do-va
ccines-work (2020)
 Basics of vaccine immunology

Source:
https://www.who.int/news-room/feature-stories/detail/how-do-va
ccines-work (2020)

The impact of vaccination on selected diseases in the UK

Source: (Pollard & Bijker, 2021)
 Vaccine mechanism of action
1. Introduction of the Antigen
2. Activation of the Immune System
3. Antibody Production
4. Formation of Immune Memory
5. Long-term Protection

Vaccine mechanism of action

Source: Tian et al., (2022)
 Types of vaccines
1. Live attenuated

Live attenuated vaccine

Source: Pfizer
 Types of vaccines
2. Inactivated vaccines

Inactivated vaccine
Source: Pfizer
 Types of vaccines
3. Subunit vaccines

Subunit vaccine
Source: Pfizer
 Types of vaccines
4. mRNA vaccines

mRNA vaccine
Source: Pfizer
 Vaccine Development
and Clinical Trials

Schematic representation of vaccine development and delivery.

Sources: vfa, NaLI | Illustration: Emde Grafik
Vaccine adjuvants and new strategies for
improving vaccine safety
Source: Han, 2015
Reference
Basmaciyan, L., Bon, F., Paradis, T., Lapaquette, P., & Dalle, F. (2019). Candida albicans interactions with the host: crossing the intestinal epithelial
barrier. Tissue Barriers, 7(2), 1612661.
Lopes, J. P., & Lionakis, M. S. (2022). Pathogenesis and virulence of Candida albicans. Virulence, 13(1), 89-121.
Naglik, J. R., König, A., Hube, B., & Gaffen, S. L. (2017). Candida albicans–epithelial interactions and induction of mucosal innate immunity. Current
opinion in microbiology, 40, 104-112.
Richardson, J. P., Ho, J., & Naglik, J. R. (2018). Candida–epithelial interactions. Journal of fungi, 4(1), 22.
Talapko, J., Juzbašić, M., Matijević, T., Pustijanac, E., Bekić, S., Kotris, I., & Škrlec, I. (2021). Candida albicans—the virulence factors and clinical
manifestations of infection. Journal of Fungi, 7(2), 79.
Alsayed, S. S. R., & Gunosewoyo H. (2023). Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets. International Journal
of Molecular Sciences, 24: 1-23.
Russell, M. (2024). Influenza A Virus Host-Pathogen Interactions and the Host Immune Response (Innate and Adaptive).
https://app.biorender.com/biorender-templates/t-65f31b3f46a57155be48bb44-influenza-a-virus-host-pathogen-interactions-and-the-host-im
Mifsud, E. J., Kuba, M., & Barr, I. G. (2021). Innate immune responses to influenza virus infections in the upper respiratory tract. Viruses, 13(10),
2090.
Mtambo, S. E., Amoako, D. G., Somboro, A. M., Agoni, C., Lawal, M. M., Gumede, N. S., Khan, R. B. & Kumalo, H. M. (2021). Influenza viruses:
harnessing the crucial role of the M2 ion-channel and neuraminidase toward inhibitor design. Molecules, 26(4), 880.
Francis, M. E., King, M. L., & Kelvin, A. A. (2019). Back to the future for influenza preimmunity—Looking back at influenza virus history to infer the
outcome of future infections. Viruses, 11(2), 122.
Skelton, R. M., & Huber, V. C. (2022). Comparing influenza virus biology for understanding influenza d virus. Viruses, 14(5), 1036.
Klein, S., Golani, G., Lolicato, F., Lahr, C., Beyer, D., Herrmann, A., Wachsmuth-Melm, M., Reddmann, N., Brecht, R., Hosseinzadeh, M., Kolovou, A
& Chlanda, P. (2023). IFITM3 blocks influenza virus entry by sorting lipids and stabilizing hemifusion. Cell Host & Microbe, 31(4), 616-633.
Reference
Hutchinson, E. C. (2018). Influenza virus. Trends in microbiology, 26(9), 809-810.

Riensya, B. A. (2019). Imunopatogenesis Tuberkulosis. Pekanbaru: Fakultas Kedokteran Universitas Riau

Adiyaksa, J., & Sjatha F. (2024). Development of Vaccine Candidates against Mycobacterium tuberculosis in 2019-2023. Manuju:
Malahayati Nursing Journal, 6(5): 1984-1906.
Petrova, V. N., & Russell, C. A. (2018). The evolution of seasonal influenza viruses. Nature Reviews Microbiology, 16(1), 47-60.
Krammer, F. (2019). The human antibody response to influenza A virus infection and vaccination. Nature Reviews Immunology, 19(6),
383-397.

Finn, C. M., & McKinstry, K. K. (2024). Ex Pluribus Unum: The CD4 T Cell Response against Influenza A Virus. Cells, 13(7), 639.

Guthmiller, J. J., Utset, H. A., & Wilson, P. C. (2021). B cell responses against influenza viruses: short-lived humoral immunity against a
life-long threat. Viruses, 13(6), 965.

Swidergall, M., & LeibundGut-Landmann, S. (2022). Immunosurveillance of Candida albicans commensalism by the adaptive immune
system. Mucosal immunology, 15(5), 829-836.
Kaur, G., Chawla, S., Kumar, P., & Singh, R. (2023). Advancing vaccine strategies against Candida infections: exploring new frontiers.
Vaccines, 11(11), 1658