Vaccines (Totonchy)

What placebo did Oxford/Astrazenica use in their phase I/II trial of ChAdOx1 for COVID19?

(Results published July 20, 2020 in The Lancet)

A different vaccine

• The Oxford/AZ phase I/II trial used the approved MenACWY vaccine as placebo for this study. This was to prevent participants from guessing they were in the placebo group due to a lack of reaction to the shot

Could manufacturers have used an internally controlled study or a surrogate endpoint for phase 3 trials of the COVID19 vaccines in 2020? Why or why not?

No

• These approaches require that you have a blood test (or similar) that can determine whether a person is immune or not. This is called "immune correlates of protection" We did not know enough in 2020 to use this approach

It is 2023 and Moderna is testing a booster vaccine for COVID19 with a different mRNA sequence. What endpoint should they use for the study?

Surrogate

• Efficacy endpoint would have been hard due to high pre-existing immunity and poor understanding of cross-protection

You are testing a novel, adjuvanted subunit vaccine against meningococcal disease in adolescents (11-12 years) in the United States. What would be the most appropriate thing to administer to the subjects in the control arm of the study?

None, use an internally controlled study

• The disease's rarity makes efficacy studies impractical, so surrogate markers are used

• Internally controlled studies reduce bias but don't allow direct side-effect comparison between new and old vaccines

True or false: Data from the VAERS system can directly indicate whether a vaccine is causing an adverse event.

False:

• VAERS is an unsolicited reporting system providing anecdotal data that requires epidemiologists to interpret

• Understanding vaccine safety needs context, like comparing reported events to their normal population ris

Which of the following is an example of post-marketing surveillance successfully identifying risks for vaccines?

• Excess febrile seizure risk with MMRV in children under 2

• Intussusception risk in infants receiving RotaShield

• Increased risk of GBS with Shingrix

• All of the above

All of the above:

• MMRV: 1/10,000 risk found in VSD data; now only for the second dose at 4-5 years

• RotaShield: Intussusception risk (1-2/10,000) found via VAERS; vaccine withdrawn

• Shingrix: Rare GBS risk (6/million) identified in VSD data; warning added but no recommendation changes

When is it unethical to use an inactive placebo in a study?

When there is an established standard of care for the target group

Why might a non-inactive placebo be used in a study?

To mimic reactogenicity and preserve blinding, especially if risk behaviors affect disease risk in an efficacy study

What are immune correlates of protection?

Information about what a protective immune response looks like, influencing the choice of surrogate or efficacy endpoints

Why might a surrogate endpoint be needed for rare diseases?

Rare diseases require a surrogate endpoint if correlates of protection are unknown to avoid a large or prolonged study

What is the main challenge with passive safety surveillance like VAERS?

It can be difficult to determine if a safety signal is real or just coincidental with normal life events

What is an advantage of active safety surveillance like VSD?

It provides complete data and is internally controlled for each patient

WHERE is the antigen?

We get different immune responses when antigens are presented from outside cells vs. antigens being made inside cells

WHAT is the antigen?

We get different immune responses with protein vs. non-protein antigens

HOW is innate immunity being activated?

A vaccine won't work unless is has danger signals that activate innate immunity in a way that primes an adaptive response. In a vaccine this is called adjuvant activity and the thing that does this is an adjuvant

Which disease requires the highest vaccine effectiveness and vaccination rate to achieve herd immunity and why?

Measles

• Measles, one of the most contagious diseases (R₀: 12-20), requires at least 95% vaccination coverage with a 97% effective vaccine to achieve herd immunity

Did the original trials for the mRNA vaccines tell us whether they could be used to achieve herd immunity for COVID19?

No

• Herd immunity limits pathogen transmission, but the mRNA vaccines' original phase 3 trials only focused on symptomatic disease. Given COVID-19's short incubation and pre-symptomatic spread, herd immunity is unlikely

Which vaccines use the AS01 adjuvant system? Why is this adjuvant particularly needed for these vaccines?

Shingles (Shingrix) and Malaria

• Both vaccines use the AS01 adjuvant, combining MPLA (activates TLR4) and QS-21 (activates innate immunity via an unknown mechanism)

• AS01 effectively stimulates CD4 T cells, crucial for strong responses in older adults (e.g., Shingrix) and young children (e.g., malaria)

Which vaccine uses a dedicated adjuvant compound?

Novavax covid vaccine

Which vaccine formulation might be expected to generate CD8+ T cell responses?

mRNA vaccines

• mRNA vaccines enable protein antigens to be made inside cells, improving MHC class I processing and enhancing CD8+ T cell responses. Other vaccines that do this effectively include live attenuated, DNA, and viral vectored formulations.

In January of 2023 a new, deadly pandemic virus emerges that is has an RNA genome but is not genetically related to any known virus. What vaccine strategy is likely to yield an effective vaccine in the shortest time?

Whole inactivated vaccine

• This approach doesn't always provide the best immunity and requires growing large amounts of the virus, but it requires minimal knowledge about the pathogen or the immune system's response

Which COVID19 vaccine formulation is most likely to make an immune response that is the most durable against viral mutation/ variants?

• mRNA

• Whole inactivated (not the best)

• Viral vectored

Measles is an RNA virus with a high mutation rate. Why has the same measles vaccine worked with the same effectiveness for decades?

Because the measles virus can't change the main antigen the immune system recognizes

Novavax is used "traditional" vaccine formulation strategies for COVID19, why did it take so much longer for them to develop their vaccine candidate?

Because their strategy requires details of protein structure that wasn't available early in the pandemic

What is herd immunity?

Herd immunity is achieved when enough of a population is immune to a pathogen, limiting its spread within the community

What three factors determine the threshold for achieving herd immunity?

1. The contagion level of the pathogen (how easily it spreads)

2. The effectiveness of the vaccine

3. The percentage of the population vaccinated

How does the contagiousness of a pathogen (R₀) affect herd immunity?

The more contagious the pathogen, the higher the threshold for herd immunity. For example, if R₀ = 2, a 50% immunity level is needed to limit spread

How do vaccine effectiveness and vaccination uptake affect herd immunity?

To achieve herd immunity, vaccine effectiveness × vaccination uptake must be greater than the required immunity threshold (e.g., 0.5 for R₀ = 2)

What activates innate immunity in live attenuated vaccines?

In live attenuated vaccines, the pathogen-associated molecular patterns (PAMPs) from the live pathogen activate innate immunity

How do mRNA vaccines activate innate immunity?

The mRNA itself activates pattern recognition receptors (PRRs) in the body, triggering innate immune responses

How do viral-vectored vaccines activate innate immunity?

The viral vector and its vaccine DNA activate pattern recognition receptors, stimulating innate immunity

How do inactivated and protein subunit vaccines activate innate immunity?

They require dedicated adjuvants to enhance immune activation since they lack natural PAMPs

What type of immune response is expected if vaccine antigens are outside cells (e.g., protein subunit or inactivated vaccines)?

Antibody response only. CTL (cytotoxic T lymphocyte) response is unlikely because the antigens are not inside cells

What type of immune response is expected if vaccine antigens are inside cells (e.g., live attenuated, viral vectored, or mRNA/DNA vaccines)?

Antibody + CTL response. CTL responses are more likely because the antigens are processed by the cells and presented on MHC class I, triggering T cell activation

What is an advantage of whole microbe approaches?

• Whole microbe approaches are useful when there is insufficient knowledge about the best antigens to target

• They provide a broader immune response since they expose the immune system to all potential antigens from the pathogen

What is a disadvantage of whole microbe approaches?

They may carry a higher risk of side effects or complications because they involve using the entire pathogen, which could cause more diverse immune reactions, particularly in immunocompromised individuals

What is an advantage of antigen selection (subunit or molecular) vaccines?

• They are safer for a broader population since they target specific antigens, reducing the risk of unwanted immune reactions

• They are more effective when the best antigen for targeting is identified

What is a disadvantage of antigen selection vaccines?

These vaccines require detailed knowledge of the pathogen’s key antigens. If the wrong antigens are chosen, the vaccine may not be effective in providing immunity

How does the mutation rate of a pathogen affect vaccine durability?

High mutation rates increase the likelihood that a pathogen can evade immune responses, potentially reducing the effectiveness of a vaccine over time

How do whole microbe vaccine approaches handle pathogen mutation?

Whole microbe vaccines target multiple components of the pathogen, which makes it harder for the pathogen to mutate and evade the immune response, resulting in better durability

How can antigen selection improve vaccine durability for subunit vaccines?

If the selected antigen is critical to the pathogen's function and cannot easily mutate, it can minimize the risk of the pathogen evading the immune system, improving the vaccine's long-term effectiveness

What happens if a pathogen targets the wrong antigen in a subunit vaccine?

If an antigen is not critical or is prone to mutation, the vaccine may become less effective over time as the pathogen adapts and mutates to evade immune recognition

Why are protein subunit vaccines slow and laborious to develop?

Protein subunit vaccines require making the protein in a lab and need detailed structural information to ensure the protein resembles the natural pathogen for an optimal immune response

How do mRNA/DNA/viral vectored vaccines differ from protein subunit vaccines in terms of development?

mRNA/DNA/viral vectored vaccines use the recipient's cells to produce the protein from a genetic sequence, bypassing the need to make the protein in the lab, speeding up development

What is the main requirement for mRNA/DNA/viral vectored vaccines during formulation?

The only requirement is the genetic sequence encoding the target protein, which allows the recipient's cells to produce the protein and elicit an immune response

What is a key advantage of molecular vaccination strategies (like mRNA/DNA) over protein subunit vaccines?

Molecular vaccines are faster to develop because they don't require protein production in a lab; instead, cells inside the recipient make the protein themselves based on the provided genetic sequence