Thu, 11/04/2021 - 20:28
Dear colleagues,
Today, I summarize some recent short papers in NEJM and I’ll discuss the progress on intranasal vaccines. Also a warning about Ivermectin.
Update on vaccines in clinical use
Ep 186-1: Linda Stuart 7 Oct NEJM a didactic overview of on mRNA vaccine modifications
Ep 186-2: Reis 20 0ct NEJM on excellent vaccine effectiveness of Pfizer in adolescents
Ep 186-3: Seikh 25 Oct NEJM Protection against death by Delta from Pfizer and Astra-Zeneca in Scotland between April and August: for various age groups, after full vaccination > 90 % (see Table 1).
Ep 186-4: Dagan 27 Oct NEJM Risk of myocarditis in 16-39 yrs
- After Pfizer mostly in men: 8.62 excess cases per 100,000
- During infection both men and women: 11.54 per 100,000
Ep 186-5: Collier 15 Oct NEJM Different kinetics of Ab and T responses after mRNA and Adeno vaccine.
Antibody and neutralization:
- BNT162b2 and mRNA-1273 vaccines: by high peak antibody responses that declined sharply by 6 months and further by 8 months. Antibody titers in mRNA-1273 vaccine generally higher than BNT162b2 vaccine.
- Ad26.COV2.S (Janssen) vaccine induced lower initial antibody responses, but these responses were relatively stable over the 8-month follow-up.
T cell responses:
- CD4 T similar and low for all 3 vaccines
- CD8 T 10 X higher for AD26.COV2.S as compared to mRNA vaccines.
Ep 186-5 B: Interestingly, Polinski in medRxiv in an observational US study on single dose Janssen show a high efficacy (around 80 % against hospitalization), which is stable over April-July, including in the Delta wave.
IVERMECTIN
Ep 186-6: Temple 20 Oct NEJM on 21 person with toxic effects from Ivermectin, taken as prevention or treatment in dosage between 7 and 125 mg.
Symptoms: gastro-intestinal, hypotension, confusion, ataxia, seizures.
Outcome: 6 hospitalized; 5 ICU; none died.
Intranasal vaccines
Two reviews:
Ep 186-7 : Rita Rubin 14 Oct JAMA viewpoint on intranasal vaccines.
- Format = live attenuated viral vector that incorporates the Spike, not mRNA
- Theoretical advantage = blocking infection at the portal of entry (while systemic vaccines protect against disease, less against infection).
- Several promising preclinical results (see below)
- Several phase 1 trials ongoing, but the one by Altimmune (using an Adenoviral vector) has been stopped, because of too low immunogenicity. No formal publication, only press release https://www.biospace.com/article/releases/altimmune-announces-update-on-adcovid-phase-1-clinical-trial/
Ep 186-8: Choudhary Sept In J Surg makes a (theoretical) balance of intranasal vaccines:
Advantages: More convenient, easy, needle free administration, often a single dose, at the site of infection, providing a broad mucosal immune response (IgG, IgA, T cells), which may prevent infection and transmission. High compliance and global access, since no freezer required.
Drawbacks: Safety issues because mostly live attenuated (e.g. Bell’s palsy). Children may “sneeze it out”. Systemic immunity may be weaker and overall more rapidly waning.
A nice table of ongoing human phase 1 trials and a nice didactic figure.
Some recent animal studies
Ep 186-9: Fisher Oct Nat Comm evaluates the (human) Astra-Zeneca vaccine (AZ1222 or ChAdOx COVID-19, based on Wuhan Spike) intramuscularly (IM) and intranasally (IN) in hamsters, challenged with alpha and beta variants (VOC):
After single IM vaccination and IN challenge with alpha or beta
- Almost 10 x lower neut titers against beta as compared to alpha (Fig 1)
- Nevertheless almost perfect protection against viral replication and pathology of the lungs after alpha (Fig 2 and 3) and beta infections (Fig 4 and 5) alike
Comparison between IM and IN vaccination and IN challenge with beta (Fig 6)
- Equally protective in the lung
- IN vaccination lowers viral shedding (from upper resp tract), while IM has no significant effect
Ep 186-10: a review on Newcastle Disease Viral (NDV) vector use and two papers with Spike incorporated NDV in hamsters.
Ep 186-10 A: Shrivani (2020 Pathogens) NDV or avian paramyxovirus-1 is a negative strand RNA virus (like Influenza), but NDV has a single non-segmented genome (while influenza is segmented).
The “attenuated” strains (LaSota or B1 with low fusion capacity) are non-pathogenic in non-human primates and humans, but have been used in oncolytic therapies, where they selectively cause apoptosis of tumor cells.
These viruses are non-transmissible and well tolerated. They do not recombine and have an exclusively cytoplasmic cycle. Their natural habitat is the respiratory tract, where they induce strong immune responses.
The construction of a vaccine vector is well explained in Fig 1. “Reverse genetics” is used here: the vaccinal gene is introduced in the complementary DNA form of the (+) RNA, usually in between the Polymerase and Membrane gene. A live attenuated vaccine is produced.
Ep 186-10 B: Sun (Octo 2021 Nature Comm) propose an NDV expressing a membrane-bound prefusion stabilized SARS-CoV-2 spike protein (by introducing 6 prolines: hexa-proline or NDVHXP-S).
Vaccinating twice IM with inactivated NDVHXP-2 or twice IN with live NDVHXP-2 effectively protected against challenge in the hamster model.
For the IM vaccine, protection was also shown against the beta and gamma VOC.
For the IN vaccine, nasal swab (shedding) was also blocked. Ep 186-10 C: Warner (Oct 2021 IScience) used a slightly different Spike (no proline mutations):
Twice IN vaccination in hamsters also protected the animals against (severe) disease after challenge and strongly reduced the viral titers in the lung and nasal swabs.
Interestingly, this vaccine could be lyophilized, without losing activity.
Ep 186-11: VSV vector
Ep 186-11 A: Goudong Liu (2020 Pathogens) describes the successful development of Vesiculo Stomatis Virus (VSV) into a viral vector. VSV is also negative strand non-segmented RNA virus and can be transformed into a viral vector by replacing the VSV glycoprotein (G) by that of another virus.
Thus a “replication competent” EBOLA vaccine has been constructed (VSV-EBOV) that needs to be injected only once for a durable protection, without safety issues.
Many other VSV-based vaccines are in the pipeline, including against Marburg, Lassa, Nipa and Hendra, Zika and Crimean Congo Hemorrhagic Fever.
Finally, several labs are developing intramuscular non-replication-competent VSV- Corona Spike vaccines for SARS-COV-1, MERS and SARS-CoV-2 with one already in human phase 1:2. https://clinicaltrials.gov/ct2/show/NCT04608305
Ep 186-11 B: O’Donnel (bioRxiv Sep 2021) shows that single dose intra-nasal or intra-muscular application of Spike expressing VSV protects hamsters against challenge already 10 days after vaccination. There is also good activity against the alpha and beta VOC
Conclusion: Various viral-vector (ChAd, Newcastle and VSV) based intranasal SARS-CoV-2 Spike Vaccines are in preclinical development. A few are in human phase 1 and 2, but one based on Adeno has been stopped.
Best wishes,
Guido
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