Covid-19 Vaccine Updates

Latest updates on COVID vaccines: 5 August 2021

A/Prof Paul Griffin

• Director of Infectious Diseases, Mater
• Medical Director and Principal Investigator, Nucleus Network
• Director and Scientific Advisory Board Member, Immunisation Coalition

Comparison of Leading Vaccines

Efficacy against severe COVID19 infection:

• Pfizer >90%
• Astra Zeneca approx. 100%
• Moderna approx. 100%
• Novavax approx. 100%

Interval between doses – 2 doses

• Pfizer 3 weeks
• Astra Zeneca 12 weeks but can be brought forward to 4 weeks
• Moderna 4 weeks
• Novavax 3 weeks

Is Pfizer better than AZ?

Initially reported efficacy was 95% for Pfizer vs mid 70% (60-90%) for AZ

• Pfizer study was large phase 3 (>43 000)
• AZ study was smaller 11 500
• Pooled data from 4 trials
• Poorly standardised dosing interval
• Issue with measurement of dose so a large dose/small dose cohort was included
• Overall efficacy of 70%
  • Some fixated on short dose/short dose of 62.1%
  • But it was the interval that was important

Post-approval studies

Lancet 3 March 2021

• First dosage effectiveness higher with AZ than Pfizer 80 vs 71

Preprint 2 Mar 2021 – older adults, England >7.5 million

• Pfizer 61% at 28-34 days and plateaued
• AZ 60% at 28-34 days and increased to 75% from day 35 onwards

Lancet preprint 19 Feb (Scotland 5.4 million people)

• First dose Pfizer effect 85%
• AZ effect 94%

However not valid to compare between different trials

• No proper head-to-head comparison
• The post approval studies comparing are probably a better indication
• Many actually show that in some ways AZ may be superior

Is Pfizer better than AZ?

No

No head to head trials done.

Real world experience suggests basically same efficacy.

Adverse effect summary from clinical trials

Local pain is common

• But is mostly mild and short-lived
• Occurs in 70-80% of recipients
• Mostly not higher after 2^nd dose
• Mostly less in elderly

Systemic effects less commonly reported

• Typically less than 50%
• More common in younger patients <55 years
• Fatigue and headaches most common
• Followed by muscle aches and chills
• Higher with first dose of AstraZeneca and increase with second dose for Pfizer

Top 10 reported reactions

• Dizziness
• Lethargy
• Nausea
• Joint pain
• Fatigue
• Injection site reaction
• Chills
• Fever
• Muscle pain
• Headache

Thrombosis-Thrombocytopenia Syndrome TTS

Important distinction between TTS and ‘clotting’

TTS is thrombocytopenia = low clotting cells with thrombosis = clotting

Increasing evidence immune system mediated

Similar to heparin-induced thrombocytopaenia

Antibody activated platelets – PF4 antibodies. Platelets release microparticles that activate thrombin causing thrombosis. Traditional clots are NOT a risk factor.

Features

            Occurs between day 4 and day 28

            Symptoms not subtle: severe headache or abdominal pain

Outcomes

            Initially concern mortality 25-30%

            Now <5%

                        Better at recognising and managing

Actual contraindications

1. Past history of CVST (cerebral venous sinus thrombosis)
2. Past history of HIT (heparin-induced thrombocytopaenia)
3. Past history of idiopathic splanchnic (mesenteric, portal and splenic) venous thrombosis
4. Anti-phospholipid syndrome with thrombosis
5. People with contraindication to COVID19 vaccine
   1. Anaphylaxis to a previous dose of COVID19 vaccine AZ or to an ingredient of the vaccine
   1. Thrombosis with thrombocytopaenia occurring after first dose of AZ.
   1. Other serious adverse events attributed to first dose of COVID19 AZ vaccine.

NOT contraindications

1. History of venous thromboembolism in typical sites such as deep vein thrombosis or pulmonary embolism.
2. Predisposition to form blood clots such as those with Factor V Leiden or other non-immune thrombophilic disorders.
3. Family history of clots or clotting conditions.
4. Currently receiving anticoagulant medications.
5. History of ischaemic heart disease or cerebrovascular accident.
6. Current or past history of thrombocytopaenia.

Benefits of AZ vs Risks of TTS

Benefits Highly effective vaccine

Nearly 100% reduction in chance of progression to severe disease

80-90% reduction of symptomatic disease 50-67% reduction in transmission

Risk of severe COVID19 may be low at the moment       

Unlikely to be the case forever

Also increases with increasing age (so benefit greater)

Risk of not vaccinating

• Rely on border closures/lockdowns/long period of quarantine

• Sars-Cov-2 will return and when it does it is too late to vaccinate (e.g.: India)

Population level benefit

Reduced risk of establishing community transmission

Protection of those not able to be vaccinated or who don’t respond

Local production

AZ produced locally and not susceptible to supply constraints of messenger RNA.

• Stable

Much less complex logistics facilitates more community based and widespread administration.

TTS Risk

• About 1-2 per 100 000

• But mortality is less than 5%. Improvement in identification and management have improved outcomes.

• TTS risk decreases with advancing age.

• Hence an age cut-off reduces risk.

• Overall side effect profile otherwise favourable and comparable to other vaccines.

Other issues to consider in TTS

• Clotting is common

• Annual incidence is over 10 million globally

           

In Australia

• 17000 clots per year

• 50 people per day

• 8% risk of developing at some stage in lifetime

 Biases

• Every case of anything evenly remotely associated with thrombosis

• Reported widely

• Assumed related

  Loss of perspective

• Anaesthetic: risk of death 1 in 57000

• Annual road toll deaths 1133

• Total cases of TTS in Australia now at 90 (54 confirmed)

• Only 35 met the tier 1 CDC criteria

• With only 6 deaths

• Out of 6.3 million doses

• Pfizer has a similar risk of myocarditis/pericarditis

AZ thromboembolic issues / Chance in a million

Serious harm due to vaccine side effects: 

• 25 yr old 11 in a million
• 4 in a million in 55 yr old

Dying with coronavirus:

• 25 yr old 23 in a million            
• 800 in a million in a 55 yr old

Dying due to accident or injury:

• 25 yr old 110 in a million          
• 180 in a million in a 55 yr old

Dying in a road accident:

• 25 yr old 38 in a million
• 23 in a million in a 55 yr old

Potential benefits vs Risk of AZ vaccination for 100 000 people with low exposure risk (based on COVID19 incidence of 2 per 10 000 roughly UK March 2021)

ICU admission due to COVID19 prevented every 16 weeks

Age 20-29         0.8

Age 30-39         2.7      

Age 40-49         5.7      

Age 50-59         10.5

Age 60-69         14.1

Serious harm due to AZ vaccine

Age 20-29         1.1

Age 30-39         0.8      

Age 40-49         0.5

Age 50-59         0.4

Age 60-69         0.2

Risk of blood clots

• AZ Vaccine 4 cases in 1 000 000 = 0.004%
• Oral contraceptive pill
• 500-1200 cases in 1 000 000 women = 0.05% to 0.12%
• Smoking 1 763 cases in 1 000 000 smokers = 0.18%
• COVID Infection – 165 000 cases in 1 000 000 cases = 16.5%

COVID19 Vaccines in Australia- Clinical Trials

Serum Institute of India

• Phase 1 commenced 1 Sept 2020

Symvivo

• Phase 1 commenced late last year

Tetherex

• Preclinical data suggests likely to be effective intranasal

Other trials

Skin

Zydus

DNA based skin patch stable at room temp, phase 3 Jan 2021

Inovio

Takis Biotech and Rottapharm Biotech

BioNet-Asia and Australia-based Technovalia

Nasal

Benefit: mucosal response leading to transmission blocking

Limitation: need potent vaccine to generate sufficient response

University of Hong Kong/ Xiamen/Wantai

Phase 2

Others include ImmunityBio, Altimune

Oral

Vaxart – San Francisco based

ImmunityBio

Symvivo

Australian COVID-19 Vaccine Supply

4 vaccine supply deals (total 169.8 million doses)

Pfizer/BioNTech

Approved 25 Jan

10+10+20 million

AstraZeneca

Provisionally approved 16 Feb

53.8 million

50 million manufactured onshore

Novavax

Phase 3 still underway

51 million

Moderna

Agreement announced 13 May

Not yet approved in Australia

25 million

10 million in 2021

15 million updated variant booster 2022

The Doherty Institute modelling indicates that vaccinating around 70% of the population aged 16 and over may allow Australia to transition to Phase B of Australia’s National COVID19 Response.

With vaccine coverage around 70% strict lockdowns will be unlikely. Low case numbers can be maintained with light restrictions which ensures test, trace, isolate, quarantine measures are most effective.

Vaccine effectiveness estimates (% reduction)

Two doses of AZ vaccine are comparable to two doses of Pfizer for reducing hospitalization, ICU admission and death.

Pfizer after 2 doses

• Symptomatic infection reduction 83%
• Hospitalisation reduction 87%
• ICU admission 87%
• Mortality 92%

AZ after 2 doses

• Symptomatic infection reduction 61%
• Hospitalisation reduction 86%
• ICU admission 86%
• Mortality 90%

Why are so many vaccinated people getting infected?

Vaccines are highly effective, reducing rate of transmission by 50%.

If number of people vaccinated high, then even though proportionately the number infected goes down, absolute numbers higher in vaccinated than unvaccinated – a recognized paradox.

Fully vaccinated infected people

• Less likely to pass it on
• Less likely to get symptoms
• Much less likely to get really sick
• Therefore the benefits of vaccination should remain abundantly clear.

Risk of infection increased in some countries in vaccinated people relative to their unvaccinated vulnerable people

• Not required to continue strategies such as wearing of masks
• Their perception of risks goes down and less likely to social distance
• Allowed to move around more freely

Therefore we are not comparing like for like.

Longevity and requirement for boosting

• The more boosters required and the shorter the interval the lower our probability of achieving sufficient coverage
• May be addressed by 2^nd and 3^rd generation vaccines
• Will almost certainly need boosters to increase immunity, and to address variants
• May be like the flu vaccine – combined flu / Covid-19 vaccine coming

Variants of Concern

All living cells have errors when reproducing. Higher organisms are good at repairing these errors. Viruses and bacteria are not so good at fixing them so mutations are common. SARS-CoV2 actually mutates relatively slowly compared to other viruses.

These mutations often result in a loss of ‘fitness’ and simply fade away. When they confer a benefit the new strain or variant can take over and replace the previous one.

Variants will continue to emerge. Whilst some may be more infectious and vaccine efficacy may be reduced the current vaccines have been effective in all strains (alpha (UK), beta (South Africa), gamma (Brazil) delta (India) and kappa (India).

Ongoing challenges

Misconceptions

Safety concerns: Many reports misconstrued as evidence of lack of safety, coincident events reported as related.

Speed: Commonly reported that speed coming at the cost of safety and insufficient testing.

Lack of efficacy: from clinical trials vs variants, in terms of preventing infection/transmission

No benefit: given our level of control with other strategies

            Insufficient perception of risk

Conspiracy theories: virus created for some agenda

Other common misunderstandings

            Illness is mild, therefore why would we vaccinate

            Strains and mutations mean vaccine won’t work

Predictions

First generation vaccines will make a huge difference.

• But will have insufficient coverage to facilitate really opening up

Need to link being vaccinated with deserved freedoms

• Fully vaccinated should be allowed to travel/except from border restrictions

Utilise technology

• Apps to assist contract tracing, proof of vaccination, managing cases at home and home quarantine.

• Rapid testing

Next Generation vaccines and boosting

• New vaccines will come to address shortcomings of current vaccines particularly blocking transmission.

• Combination vaccines e.g.: with flu

Despite above, virus likely endemic (i.e.: here to stay)

• Need to use above to learn to live with it

• Need to revise our zero Covid-19 focus and learn to minimise impact and balance it with quality of life.

Other targets more reasonable

• Common sense can begin to be a factor e.g.: risk-based quarantine, even at home

Therapies will also be important

• To improve outcomes

• Hopefully to reduce transmission also

Travel

• Should start to be allowed soon in more hubs/bubbles e.g.: NZ to Singapore etc.

• Broader travel should follow if appropriate justification and mitigation

• Free unrestricted recreational travel still a few years away

When we do open up, the cases will come

• That’s why we need sensible response particularly having everyone vaccinated.