MICR5817 L5: Current/Future Vaccine Development Challenges 8/3/26

What are the implications of this current issue in vaccine development?

-Is the disease important to prevent?

-Surveillance for infectious diseases

-True burden of disease

-Potential market

What are the implications of this current issue in vaccine development?

-Pathogenesis: how the disease occurs

-Correlates of protection against the disease

-Best candidates

-Understanding structure of the microbe and the roles of different antigens

-Developing the best animal models to replicate the human disease(s)

What are the implications of this current issue in vaccine development?

-Optimal vaccine dose, formulation and schedule

-Need to efficiently predict balance of immunogenicity and reactogenicity

-Predictive biomarkers for successful Phase 3 program

What are the implications of this current issue in vaccine development?

-Efficacy in the target population(s)

-Cost effectiveness

Detailed information to allow licensure and use on national / regional programs

What are the implications of this current issue in vaccine development?

-Is it effective and safe in the real-world populations in the long term?

Need for ongoing pathogen, disease and safety surveillance

What reactions happened to people who received the inactivated RSV vaccines and experienced increased/enhanced disease severity?

-Eosinophilia shows evidence of Type II allergic response instead of protective reaction

-Fusion protein allows virus to infect cells

List all the trial versions of the RSV vaccine

1) Subunit vaccines

2) Live attenuated vaccines

3) Polypeptide vaccine

4) Vector vaccine

What type of RSV vaccine trial are these?

-Purified fusion protein with low concentration of G (PFP-1)

-PFP(PFP-2, PFP-3)

-Combination proteins F/G/M

1) Subunit vaccines

What type of RSV vaccine trial are these?

-Cold passaged, temperature sensitive -cpts248/404

-Genetically engineered vaccines -rABcp248/404ΔSH,

rA2cp248/404/1030ΔSH (Medi-559, phase II trials)

Live attenuated vaccines

What type of RSV vaccine trial are these?

-BBG2Na (aa130-230 of G protein fused to albumin binding domain of streptococcal G protein)

Polypeptide vaccine

What type of RSV vaccine trial are these?

-bPIV3-hHNPIV3-hFPIV3-hFRSV (Medi-534)

Vector Vaccine

Which RSV vaccine made it to Phase 3 trials?

None

What is the concept behind a post-fusion protein vaccine?

-Fusion protein transforms from prefusion to postfusion conformation

-Binds to host cells to pull it closer, inject RNA and replicate it

What was a major flaw with the Post-fusion RSV protein that led to strong immunogenicity but weak protection? (Insert Image P9)

-Postfusion protein form loses protective epitopes

-Antibodies cannot bind to epitopes and neutralize virus

-Resulted in a Th2 eosinophilic/allergic response

Why couldn't the Post-fusion RSV protein vaccines bind to the host cells successfully? (Insert Image P10)

-Protein was reverting to lower native energy conformation (prefusion form)

-Can't bind to host cells or inject viral RNA

How was the RSV vaccine redesigned?

-Put in extra mutations to stabilize prefusion protein

-This preserves epitopes sites for neutralizing the viral proteins with antibodies

Which Phase 3 studies of RSV vaccines in older adults is this?

-Some efficacy in pivotal Phase 3 trial in 4,500 pregnant women but failed primary endpoint

-Vaccine discontinued due to lack of funding

Novavax unadjuvanted nanoparticle F-protein vaccine (X)

Which Phase 3 studies of RSV vaccines in older adults is this?

-Promising immunogenicity in older adults & pivotal Phase 3 study of 25,000 older adults successful

-ClinicalTrials.gov Identifier: NCT04841577

-Now licensed and on NIP in Australia

GSK pre-F3 protein with AS01E adjuvanted vaccine

Which Phase 3 studies of RSV vaccines in older adults is this?

-Efficacy demonstrated in human challenge model

-Pivotal Phase 3 study of over 34,000 older adults in 7 countries successful (RENOIR) and 7,000 pregnant women (MATISSE).

-ClinicalTrials.gov Identifier: NCT05035212 - now licensed and on NIP for every pregnancy in Australia

Pfizer bivalent pre-F-protein vaccine from both RSV A & B strains

Which Phase 3 studies of RSV vaccines in older adults is this?

-Phase 3 trial of 37, 500 adults successful but shorter duration on immunity

-ClinicalTrials.gov Identifier: NCT -successful results published & licensed in Australia but not marketed

Moderna mRNA vaccine containing mRNA sequences based on RSV A & B preF proteins ü

Which Phase 3 studies of RSV vaccines in older adults is this?

-Adenoviral 26 vector with PreFusion protein with protein boost (Janssen) X

-MVA vector vaccine with multiple antigens ( Bavaria-Nordic) X

Viral vector vaccines in Phase 3 trials

Describe the trends with RSV Vaccine efficacy in older adults (INSERT IMAGE P14)

-Immune protection didn't last very long

-Later clinical trials didn't demonstrate strong protection

What is this?

-Nirsevimab and Clesrovimab

-Next generation RSV monoclonal antibodies

-Contain YTE modification in Fc region

How did next generation RSV monoclonal antibodies extend protection through passive immunization? (Insert Image P14)

-YTE mutation in Fc region allows antibodies to bind prefusion structure and epitopes

-Antibodies can successfully attack the virus

-Antibody breakdown is decreased, half-life is increased

Describe the process of how next-gen monoclonal antibodies enter and protect against the RSV (Insert Image P14)

Why do we need Phase IV Vaccine surveillance?

1) Needed to detect rarer adverse events

2) Reflects real life use of vaccine

3) Confirm effectiveness of vaccine

Describe examples of this need for Phase IV vaccine surveillance

1) Detection of rare adverse events

-Febrile convulsions, Guillan Barre syndrome, intussusception

-The development of AusVax Safety

Describe examples of this need for Phase IV vaccine surveillance

2) Reflects real life use of vaccine

-Variability in preparation, stability and storage

-Vaccines are used in more groups than pre-license studies

Describe examples of this need for Phase IV vaccine surveillance

3) Confirm effectiveness of vaccine

-New strains emergence/vaccine failure

-CDNA & NCIRS : NNDS, IPD, National Neisseria Network

-ED & GP surveillance for rotavirus, influenza

-Hospital networks: PAEDS for pertussis in infants, varicella; Flucan for influenza

What is this? (Insert Image P19)

-Influenza vaccine that caused febrile convulsions in 0.5-1% of children in 2010

-All febrile convulsions in WA were reported following the same brand

Fluvax/Fluvax Junior

What symptoms was the highly reactogenic FluVax causing to young children in 2010? (Insert Image P20)

-Very reactogenic vaccine

-Specific symptoms: fever, fatigue, vomiting, rigors

-Nonspecific: Swelling, diarrhea, rash, headache, convulsions

Why did Fluvax induce a much higher reactogenicity and accidentally drive the immune response in children?

-2 new viruses with CSLs novel splitting process

-Resulted in an increased volume of unsplit products (HA + NA)

-Residual products are more reactogenic than other vaccines in young children

True or False: Influenza vaccine coverage in WA remains suboptimal despite provision of free vaccine

True

How did PCV-13 vaccine affect the rate of PCV 3-dose vaccine failure?

-After PCV-13, PCV vaccine failures increased

-Most cases were in children over 12 mths & IPD associated with pneumonia / empyema

-Related to waning immunity after 3+0 schedule

What age did most PCV 3-dose vaccines fail at after introducing PCV-13 to infants?

Age 12-24 months

Why did infants who received the 13-valent pneumococcal conjugate vaccine experience waning immunity? (Insert Image P27)

-The infant immune system matures over 1st year of life

-Solution: Need a PCV booster at 12 months

How did the PCV-13 infant schedule change?

-Changed to 2, 4, 12 months PCV schedule

-High-risk and Aboriginal infants still need 3 infant PCV doses + booster at 12 months

-New 15 and 20-valent PCV completed Phase 3 trials, need to assess ongoing effectiveness

True or False: In Australia, extra PCV serotypes account for 28% of IPD cases in children < 5 years

True

Is this a Pneumococcal Conjugate Vaccines (PCV) or a Polysaccharide Vaccine (PPV)? (Insert Image P29)

-Protects against an individual strain

-Need to broaden coverage

PCV (Pneumococcal Conjugate Vaccines)

Is this a Pneumococcal Conjugate Vaccines (PCV) or a Polysaccharide Vaccine (PPV)? (Insert Image P29)

-Not as effective in children

-Does not stimulate immune system for protection

Polysaccharide Vaccine (PPV)

What is the theoretical impact of referencing subsequent multivalent vaccines to a previously listed vaccine? (Insert Image P30)

-Measured the Serotype AB response range

-Compared the 0.5 threshold for non-inferiority

-PCV13 and PCV20 become less effective compared to PCV7

Give examples of this future challenge/opportunity for vaccine development:

-Maximising benefits of new vaccine technologies

-Using the Omics revolution (pathogen and human)

-Custom design vaccines and adjuvants

Give examples of this future challenge/opportunity for vaccine development:

-Human challenge models

-Offer an approach to demonstrate proof of principle for vaccine efficacy

-RSV, pertussis, malaria, GAS, influenza

Give examples of this future challenge/opportunity for vaccine development:

-Dealing with pathogens with high variability between strains

SARS-CoV2, influenza, rhinovirus, pneumococcus, non-typeable Haemophilus influenzae, E. coli, GAS

Give examples of this future challenge/opportunity for vaccine development:

-Infections that evade the immune response

HIV, tuberculosis, Pseudomonas (bacterial biofilm) in Cystic Fibrosis

Give examples of this future challenge/opportunity for vaccine development:

-Most vaccine preventable deaths occur in low-middle income countries

-Other major vaccine targets are also predominantly in LMICS

-HIV, tuberculosis, malaria, Group A Streptococcus, dengue

-Pathogenesis and correlates of protection poorly defined

-Don't have a good animal model to study

Describe some examples of SARS Covid-2 vaccine design strategies (INSERT IMAGE P32)

What challenge did Covid vaccines targeting the SPike (S) protein face?

-Spike protein structure changes following binding

-Need to use pre-fusion S protein conformation to elicit neutralizing antibodies

Name some other Covid vaccine antigens/strategies that were less effective compared to the mRNA vaccine

-Inactivated virions (easier to make)

-Vaccines targeting E, M, and N proteins

Describe the pattern of emergence of new Variants of Concern in Australia, 2023 (Insert Image P33)

-Rapid replacement of pre-existing VoCs

-New strains coming in within 4-6 month periods

-Each strain is replaced by the next one

-Alpha, Delta, BA.1, BA.2, BA.4, BA.5, recombinant

What is the new vaccine for Covid-19 variants?

-Moderna XBB.1.5 mRNA vaccine

-Elicits viral neutralising activity against multiple strains

-Developed mRNA vaccines that provide broad protection compared to original Wuhan variant

What meningococcal B disease vaccine was developed using Reverse Vaccinology and Genomics?

Bexsero (GSK)

Name some a protein candidate for the meningococcal B vaccine (Bexsero) that was identified with Genomics

FHBp: Factor H binding protein (Trumenba, Pfizer)

Describe how protein vaccine candidates for meninogococcal B disease were screened before Genomics

-Screen bacteria and develop antibody

-Look at entire genome of bacteria

Describe how Genomics was used to screen protein vaccine candidates for meningococcal B disease

-Screen a list of conserved surface outer membrane proteins for potential candidate

-Find candidate that can elicit a bactericidal antibody response to different strains

How does Genomics reverse vaccinology work? (Insert Image P35)

1) Compile in silico vaccine candidate

2) Express recombinant proteins

Explain in-depth how evaluating vaccine candidates and expressing recombinant proteins leads to discovering protein targets (Insert Image P35)

1) Identify vaccine candidates in silico/simulation

2) Express recombinant proteins in E. coli

3) Identify novel surface-exposed proteins

4) Novel proteins with bactericidal activity = vaccine candidates

What is this?

-Intentional infecting a healthy adult volunteer with infectious agent

-Learn about vaccine efficacy, protection against specific strains

-Used to help select vaccine candidate

Controlled human infection model (CHIM)

How does CHIM (Controlled human infection model) work?

-Participants may be treated at a defined time (or earlier) based on symptoms

-Need to show safety and reliability

-FDA Guidance on the regulatory considerations for use in vaccine licensure

Name examples of vaccines that were tested using CHIM to supplement trials

Typhoid and intranasal pertussis vaccines

Describe the current political challenges for vaccines and list some things RFK Jr. has done

-Slashed funding for vaccine research

-Limited access for Covid-19 shots

-Ousted the head of the CDC (undertakes VPD surveillance)

-Removed ACIP committee (recommends vaccines)

Describe the current coverage of the MMR (measles, mumps, rubella) vaccine in the USA

-Overall MMR vaccine coverage fallen to 92.5%

-About 1/3 states are even lower than

Desxcribe some infections that we are trying to get vaccines to cover (Insert Image P38)

-HPV, Malaria, Typhoid, Dengue

-EID and AMR

-TB, HIV, Shigella, GBS, RSV

What did we learn from the RSV vaccine that we were able to apply to the Covid vaccine?

-We need to adapt to the prefusion protein form

-Ongoing challenges of antigen variation in target pathogens

-Better understandings of disease pathogenesis will lead to more effective vaccines

What two factors are critical to a successful immunization program?

Vaccine safety + maintaining community confidence

What should we invest into so we can provide new opportunities for diseases with no current vaccines?

Genomics, novel vaccine technologies

What are some basic challenges for vaccines?

Extremes of age, immunocompromised people