Possible vaccines/treatment(s) for Coronavirus

[Aladdin]

I’m not sure that’s quite accurate, or rather it might be too accurate for a normal interpretation of what ‘getting’ the virus means, even if it turns out not to provide sterilising immunity in any cases.

I think it’s fair to categorise the situation where one is exposed to the virus, it replicates a bit in your cells but is shut down hard by your (vaccine derived) immune response to the extent where you have no effects and have an effective zero probability of passing it on (due to negligible load and or shedding) as ‘not getting the virus’ for most purposes.

Thanks prunus
Your previous post answers my question...

 

[2hats]

I’m not sure that’s quite accurate, or rather it might be too accurate for a normal interpretation of what ‘getting’ the virus means, even if it turns out not to provide sterilising immunity in any cases.

I think it’s fair to categorise the situation where one is exposed to the virus, it replicates a bit in your cells but is shut down hard by your (vaccine derived) immune response to the extent where you have no effects and have an effective zero probability of passing it on (due to negligible load and or shedding) as ‘not getting the virus’ for most purposes.

For the sense of 'getting' such that there is active virus in your body. What your immune system does with it and how swiftly really depends on the performance of your immune system (ie response to vaccine and/or previous infection). That's going to vary (for different individuals) between "shut down hard" and progression through N generations (hence 'breakthrough').

That is quite worrying.

Not really. 'Worrying' is that it will take at least 3-5 years (optimistically) to vaccinate ~80% of the global population. Plenty of time for SARS-CoV-2 to experiment with escape strategies.

 

[Aladdin]

'Worrying' is that it will take at least 3-5 years (optimistically) to vaccinate ~80% of the global population. Plenty of time for SARS-CoV-2 to experiment with escape strategies.

Agreed..that is a huge concern.

 

[Supine]

Not really. 'Worrying' is that it will take at least 3-5 years (optimistically) to vaccinate ~80% of the global population. Plenty of time for SARS-CoV-2 to experiment with escape strategies.

where is that estimate from? I thought the plan was to have everybody vaccinated by end of next year. The industry is scaling up to produce enough to do so.

 

[2hats]

where is that estimate from? I thought the plan was to have everybody vaccinated by end of next year. The industry is scaling up to produce enough to do so.

And distribution to the end recipients? Production!=jabs in arms. Will be happy to see it done in 2 years but persons I speak/listen to in global public health seem to be talking about several years.

 

[elbows]

Regarding vaccination and transmission, this is the sort of thing they were coming up with at the end of April, based on early analysis:

One dose of COVID-19 vaccine can cut household transmission by up to half

A new study by Public Health England (PHE) has shown that one dose of the COVID-19 vaccine reduces household transmission by up to half.

www.gov.uk

 

[2hats]

A new study preprint, on vaccine evasion, out of Ravi Gupta's lab (Cambridge) suggests that B.1.617.2, delta, demonstrates a significant degree of immune evasion and fitness (compared to B.1.1.7, alpha). They found that delta was both more efficient at infecting respiratory tract cells, and exhibited more spike (facilitating enhanced virus cell entry) than alpha. Testing sera from vaccinees they found around 8-9 fold reduction in delta compared to original wild type. They estimate that delta gains a transmissibility advantage of between 10-40% and an immunity escape advantage of around 20-55% over previous variants.

Relative reductions in neutralisation by convalescent and vaccinee sera, respectively:

Looking at vaccinated healthcare workers they found that whilst severe disease was rare, transmission clusters were much larger than for previous variants.

At population scale, extensive vaccination will likely protect against moderate to severe disease and will reduce transmission of the Delta variant. However, vaccine breakthrough clusters amongst healthcare workers is of concern given that hospitals frequently treat individuals who may have suboptimal immune responses to vaccination due to comorbidity. Such patients could be at risk for severe disease following infection from healthcare workers or other staff within hospital environments. Therefore strategies to boost vaccine responses against variants are warranted in healthcare workers and attention to infection control procedures should be continued even in the post vaccine era.

DOI: 10.21203/rs.3.rs-637724/v1.

 

[2hats]

Cuban protein sub-unit vaccine Abdala (three dose regimen) reported, by BioCubaFarma, to demonstrate 92.28% efficacy to infection in clinical trials. No preprint or details as of yet.

Cuba says Abdala vaccine 92.28% effective against coronavirus

Cuba said on Monday its three-shot Abdala vaccine against the coronavirus had proved 92.28% effective in last-stage clinical trials.

www.reuters.com

 

[2hats]

Two more (refereed) studies about the super-immunity of single mRNA dose convalescents and some thoughts on the phenomena.

In the first study (Fred Hutch/UWash) prevaccination sera from recovered donors neutralised early type and sporadically neutralised B.1.351, but a single mRNA dose boosted neutralising titres against all variants (and even SARS-CoV-1) by up to 1000-fold, suggesting it will provide protection against emerging variants too. This neutralisation was not boosted by a second dose, suggesting that that could be delayed. Immunisation of naïve donors also elicited cross-neutralising responses but at lower titres, highlighting the importance of vaccinating both uninfected and previously infected persons to elicit cross-variant neutralising antibodies.

DOI: 10.1126/science.abg9175.

In the second study (Imperial) longitudinal evolution of T and B cell responses in healthcare workers vaccinated with BNT162b2, both with or without prior infection, was analysed. After the first dose individuals with prior infection showed enhanced T cell immunity, antibody-secreting memory B cell response to the spike protein, and neutralising antibodies effective against variants B.1.1.7 and B.1.351. By comparison, healthcare workers without prior infection, receiving a single dose, exhibited reduced immunity against variants. They found that single-dose vaccination after infection with a heterologous variant achieved similar levels of S1 RBD binding antibodies to two doses in naïve vaccinated individuals, along with substantial response to variants, whilst a second dose for those same convalescent individuals offered no additional enhancement.
DOI: 10.1126/science.abh1282.

In the same issue of Science, Crotty (LJI/UCSD), provides commentary and thoughts on this super-charged 'hybrid immunity' (single-dose convalescent immune response) and the key role of immunological memory - in particular the interplay of T and B cells and the epitope breadth of T cells arising from natural infection. This could point to heterologous prime-boost approaches as being the way forward.

Why does this pronounced neutralizing breadth occur? Memory B cells are a primary reason. They have two major functions: one is to produce identical antibodies upon reinfection with the same virus, and the other is to encode a library of antibody mutations, a stockpile of immunological variants. These diverse memory B cells, created in response to the original infection, appear to be pre-emptive guesses by the immune system as to what viral variants may emerge in the future. This brilliant evolutionary strategy is observed clearly for immunity to SARS-CoV-2: A substantial proportion of memory B cells encode antibodies that are capable of binding or neutralizing VOCs, and the quality of those memory B cells increases over time. Thus, the increase in variant-neutralizing antibodies after vaccination of previously SARS-CoV-2-infected persons reflects recall of diverse and high-quality memory B cells generated after the original infection.

T cells are required for the generation of diverse memory B cells. The evolution of B cells in response to infection, or vaccination, is powered by immunological microanatomical structures called germinal centers, which are T cell–dependent, instructed by T follicular helper (TFH) CD4+ T cells. Thus, T cells and B cells work together to generate antibody breadth against variants. Additionally, T cells appear to be important at the recall stage. Memory B cells do not actively produce antibodies; they are quiescent cells that only synthesize antibodies upon reinfection or subsequent vaccination. Memory B cells are increased 5- to 10-fold in hybrid immunity compared with natural infection or vaccination alone. Virus-specific CD4+ T cells and TFH cells appear to be key drivers of the recall and expansion of those SARS-CoV-2 memory B cells and the impressive antibody titers observed.

T cell responses against SARS- CoV-2 in natural infection are quite broad, and most T cell epitopes are not mutated in VOCs, indicating that the contributions of T cells to protective immunity are likely to be retained. Most of the COVID-19 vaccines in use consist of a single antigen, spike, whereas 25 different viral proteins are present in SARS-CoV-2. Thus, the epitope breadth of both the CD4+ and CD8+ T cell responses is more restricted in current COVID-19 vaccines than in natural infection, whereas hybrid immunity consists of both spike and non-spike T cell memory.

Overall, hybrid immunity to SARS-CoV-2 appears to be impressively potent. The synergy is primarily observed for the antibody response more so than the T cell response after vaccination, although the enhanced antibody response depends on memory T cells. Will hybrid natural/vaccine-immunity approaches be a reproducible way to enhance immunity? The Shingrix vaccine to prevent shingles, which is given to people previously infected with the varicella zoster virus, is impressively effective (~97% efficacy), and elicits much higher antibody responses than viral infection alone. It has long been observed that combining two different kinds of vaccines in a heterologous prime-boost regimen can elicit substantially stronger immune responses than either modality alone - depending on the order in which they are used and on which vaccine modalities are combined. This may occur with combinations of COVID-19 vaccines, such as mRNA and adenoviral vectors, or mRNA and recombinant protein vaccines. These recent findings about SARS-CoV-2 immunology are pleasant surprises and can potentially be leveraged to generate better immunity to COVID-19 and other diseases.

DOI: 10.1126/science.abj2258.

 

[elbows]

I havent had time to read about this at all yet.

 

[belboid]

Seems a bit premature. The first folk only got a vaccine 13 months ago. The AZ trial is just finishing, officially. I sent off my last swab today and have one more hospital appointment in September.

 

[2hats]

An extension of an earlier study (DOI: 10.1016/S0140-6736(21)01290-3) of young, healthy staff volunteers from the Crick/UCL looking into vaccine induced immunity. Here data from AZD1222 to compare with previous and new BNT162b2 data regarding neutralisation of several variants: early type, D614G, B.1.1.7, B.1.351, and B.1.617.2.

As reported many times for mRNA recipients, reported here for the first time, a very large immune response for convalescents after a single dose of AZD1222 was observed, producing antibody neutralising titres typically exceeding that of non-convalescents after two doses. The convalescent response had significant neutralising capability across variants (with reductions across variant types seen in line with previous studies), compared to the previously uninfected. A second dose for convalescents resulted in only a small increase in neutralisation, perhaps related to the 'slow burn' nature of the immune response to viral vector platforms.

AZD1222 recipients (median age 34 years) were found to have lower neutralising antibody titres against all tested variants compared to BNT162b2 recipients (median age 42 years). This was even more pronounced when age matched.

DOI: 10.1016/S0140-6736(21)01462-8.

 

[2hats]

On increasing the prime-boost dosing interval (here of AZD1222) and a third booster - a preprint from the Oxford Vaccine Group/Jenner on the reactogenicity and immunogenicity of such a delayed second or additional third dose in volunteers aged 18-55 years who were enrolled in the earliest phase 1/2 or phase 2/3 trials.

They found that a longer delay (here around 10 months) between first and second dose of AZD1222 lead to a significantly increased antibody titre after the second dose, higher than that seen shortly after the previous two doses. An additional third booster dose of the same induced antibodies to a level that correlated with high efficacy after second dose and boosted T cell responses (there was insufficient data on the effect of delaying the second dose as regards T cell response). Higher titre neutralising antibodies against B.1.1.7, B.1.351 and B.1.617.2 variants were induced after a third dose vaccination when compared with titres induced after the second dose.

Longitudinal results for single dose AZD1222 indicated only a moderate (~3-fold) reduction in antibody tires over the first year.

Reactogenicity was observed to be lower after the second or third dose than after the first.

DOI: 10.2139/ssrn.3873839.

 

[2hats]

Have just noticed that the UK Com-COV heterologous prime-boost study (mixing AZD1222 and BNT162b2) is scheduled to deliver first immunological data later this month (early results were purely announcements concerning safety and reactogenicity).

The Com-COV preprint on immunogenicity of heterologous AZD1222/BNT162b2 schedules has found that, in a randomised controlled trial (participants >50 years, no previous SARS-CoV-2 infection), at day 28 post-boost (day 56 post-prime) SARS-CoV-2 anti-spike IgG levels of both heterologous schedules were higher than those of the approved AZD1222 homologous schedule. This supports adopting a flexible approach in the use of heterologous prime-boost vaccination using AZD1222 and BNT162b2 vaccines.

Above: A) SARS-CoV-2 anti-spike IgG levels ; B) pseudotype virus (VSV wild type) neutralising antibody levels; and C) cellular response. Dotted vertical line represents the second dose (boost).
DOI: 10.2139/ssrn.3874014.

Note also:

Jabs stockpiled for 'mix and match' vaccine boosters later this year to help UK live with Covid

Scientists have warned it is too early to make a final decision on what vaccines should be used as boosters

inews.co.uk

 

[teuchter]

What's currently the best information on the effectiveness of the Pfizer/AZ vaccines against Delta variant, according to time elapsed since 1st and 2nd doses?

(In an ideal world - shown as risk of hospitalisation and broken down by age group, and illustrated in a nice chart or graph)

 

[2hats]

A preprint from Moderna studying mRNA-1273 performance in the face of numerous variants of concern/under investigation, VOC/VUI.

Sera from vaccinees on the standard schedule exhibited small reductions in efficacy relative to earlier D614G type for many of the VOC/VUI (performed using VSV pseudovirus assay). Notably only a 2.1-fold reduction for B.1.617.2, delta, and a 1.2-fold reduction for B.1.1.7, alpha. Reductions for P.1, gamma, and B.1.351, beta, were larger (up to 8.4-fold for beta) but all the tested variants remained susceptible to neutralisation by the mRNA-1273 elicited serum.

DOI: 10.1101/2021.06.28.449914.

 

[Brainaddict]

Don't know if this was mentioned above but Atlantic are hyping novavax as the best vaccine now and I see some new positive results came out recently: The mRNA Vaccines Are Extraordinary, but Novavax Is Even Better

In summary they claim it offers higher protection, with less side effects, and easier manufacturing and distribution, with a more tried and tested technology that people may trust more.

 

[2hats]

Don't know if this was mentioned above

Post #38,424 last week in the UK thread.

 

[2hats]

Curevac CVnCoV mRNA vaccine final data from their phase 2b/3 trial (40,000 participants) have been announced. It demonstrated vaccine efficacy of 48% against COVID-19 of any severity across all age groups and 15 variants. For participants aged 18 to 60 and across all 15 variants vaccine efficacy was 53% against disease of any severity, 77% against moderate and severe disease and it provided 100% protection against hospitalisation or death. A favourable safety profile was observed in all age groups. Curevac are now developing a second generation mRNA candidate, CV2CoV, with the aim of clinical trials later this year and regulatory approval in 2022.

CureVac - Wir revolutionieren die mRNA für das Leben der Menschen.

CureVac ist ein globales biopharmazeutisches Unternehmen mit über 20 Jahren Erfahrung in der Entwicklung der mRNA-Technologie für medizinische Zwecke.

www.curevac.com

 

[2hats]

From Ravi Gupta's lab (Cambridge) an investigation (preprint) of (BNT162b2) mRNA vaccine mediated immune response in the elderly (140 participants, median age 72, 51% female).

After the first dose there is a marked decline in responses from around 80 years onwards with a far greater propensity to no detectable neutralising response to variants, emphasising the need to avoid extending the dosage interval where VOCs are prevalent.

This neutralising response rose after the second dose but titres were still lower in 80+, who were less likely to have B cell profiles associated with neutralisation.

Furthermore T cell IFN𝛾 and IL-2 responses in 80+ were lower after the second dose.

Notably (and unfortunately in the face of VOCs) post second dose neutralising titres were higher in 80+ if the dosing interval was extended (from 3 to 12 weeks) which may, perhaps, be another point to consider in regards of the advantages of providing a booster for this cohort this autumn, coming as it would some months after the original course.

DOI: 10.1038/s41586-021-03739-1.

 

[2hats]

Just to note, Moderna mRNA-1273 now known as the brand name 'Spikevax' (Pfizer/BioNTech BNT162b2 already branded 'Comirnaty', AstraZeneca AZD1222 'Vaxzevria').

Moderna locks up Spikevax name in Europe, joins Pfizer's Comirnaty in wait for official brand approval in U.S.

Spikevax it is. Moderna has earned European Medicine Association approval for the brand name of its COVID-19 vaccine, even as it awaits an FDA decision. | Moderna has officially earned European Medicine Association approval for Spikevax as its COVID-19 vaccine brand name. Now, it joins Pfizer...

www.fiercepharma.com

 

[2hats]

A prospective cohort study (CDC and others) of ~4k health care workers, some partially/fully vaccinated with mRNA vaccines (BNT162b2 and mRNA-1273). Infection and viral load were monitored weekly via RT-PCR swabbing over four months (Dec 2020-Apr 2021) indicating attenuated viral load, reduced duration of detectability and a tendency towards a shorter period of any illness in all vaccinees.

Adjusted vaccine effectiveness was found to be 91% (95%CI: 76-97) with full vaccination and 81% (95%CI: 64-90) with partial vaccination. Where infected, the mean viral RNA load was 40% lower (95%CI: 16-57) in both partially and fully vaccinated participants than in those unvaccinated. Risk of fever was 58% lower (relative risk, 0.42; 95%CI 0.18-0.98) and the duration of illness was shorter, typically reduced by 2.3 days (95%CI: 0.8-3.7).
DOI: 10.1056/NEJMoa2107058.

 

[2hats]

I havent had time to read about this at all yet.

This is referencing DOI: 10.1038/s41586-021-03738-2 wherein significant, persistent and barely diminished germinal centre B cell activity was observed some 4 months after the second mRNA dose (BNT162b2), in turn leading to a broader, more developed repertoire of B cells potentially capable of targeting a wide range of variants. Twinned with other study observations of B cell maturation for a year+ in convalescents, this is suggestive of perhaps a long lived, robust humoral immunity (greater degree of variant immune escape, immunosuppressed and age driven immunosenescence permitting - see above).

 

[2hats]

A phase II/III trial of a new Astrazeneca vaccine candidate AZD2816, an adenoviral platform with the spike protein based on the B.1.351 (beta) variant, to assess safety and immunogenicity.

First COVID-19 variant vaccine AZD2816 Phase II/III trial participants vaccinated

www.astrazeneca.com

Now recruiting 18+ year old participants in the UK - must have already had two doses of one of the approved vaccines at least 3 months ago.

 

[2hats]

Preprint of the results of a double-blind, randomised, controlled phase 3 trial (>25k healthy participants, 18-98 years, mean age 40.1, over 20% 'at risk' ie >60 years and/or existing co-morbidity and/or high BMI) of the Covaxin/BBV152 whole virion (D614G backbone) inactivated SARS-CoV-2 vaccine (with an Algel-IMDG alum adjuvant), conducted in India. This vaccine can be stored at 2-8C and is administered as two doses, 4 weeks apart.

An overall vaccine efficacy to symptomatic infection of 77.8% (95%CI: 65.2-86.4) was observed. Efficacy to severe symptomatic COVID-19 was 93.4% (95%CI: 57.1-99.8). Efficacy to asymptomatic COVID-19 was 63.6% (95%CI:29.0-82.4). Efficacy to symptomatic delta infection was 65.2% (95%CI: 33.1-83.0).

BBV152 was well tolerated with no serious adverse events observed - perhaps the lowest of any vaccine candidates thus far.
DOI: 10.1101/2021.06.30.21259439.

 

[2hats]

A mutation to look out for - P272L in the N-terminal domain of spike (Cardiff & others). Seen in some B.1.177 lineages, it appears to escape recognition by CD8 T cell responses in both convalescent patients and vaccinees. Functionally - it removes a prominent proline that plays a key role in T cell binding. The 269-277 epitope of spike is likely significant in this respect and warrants further monitoring.

DOI: 10.1101/2021.06.21.21259010.

Not entirely unrelated: a study of healthcare workers (UCL/Barts/Imperial/others) who were repeatedly found to be PCR and serologically negative throughout the UK first wave, but they exhibited a low-level increase in an innate blood transcriptomic signature of SARS-CoV-2 infection, which suggested they experienced transient/abortive infection. Notably, they had T cells that were stronger and more multispecific than an unexposed pre-pandemic cohort, and more frequently directed against the virion replication transcription complex (RTC) than those of convalescents. T cells, that target RTC epitopes, capable of cross-recognising seasonal human coronavirus variants, were identified in these 'exposed' non-convalescents. Their pre-existing RNA-polymerase-specific T cells expanded upon SARS-CoV-2 exposure in vivo - evidence of abortive seronegative SARS-CoV-2 infection with expansion of cross-reactive RTC-specific T cells.

DOI: 10.1101/2021.06.26.21259239.

Both studies underline why designers of next generation vaccines should consider a border range of virus proteins (eg RTC, nucleocapsid) and not just focus on spike.

 

[2hats]

A press release regarding a study of efficacy of Johnson & Johnson/Janssen Ad26.COV2.S single dose viral vector to VOCs in South Africa. Efficacy to moderate to serve disease due to beta/B.1.351 is around 64%. New data suggest this vaccine neutralises both beta/B.1.351 and (to a greater degree) delta/B.1.617.2 and gamma/P.1, particularly improving over 8 months. It is not yet clear on what timescale a booster, if any, might be warranted.

Preprint pending.

Positive New Data for Johnson & Johnson Single-Shot COVID-19 Vaccine on Activity Against Delta Variant and Long-lasting Durability of Response

Demonstrated strong neutralizing antibody activity against the Delta (B.1.617.2) variant Persistent immune responses through at least eight months

www.jnj.com

 

[2hats]

From India, a preprint of a study of Covishield (ChAdOx1/AZD1222) neutralisation of delta/B.1.617.2. Evaluations of sera (4 weeks post-vaccination) from single and double dose vaccinees, both previously uninfected and infected, and breakthrough cases. The now familiar story of prior infected (and breakthroughs) with one or two doses having higher neutralising titres (and so relatively higher protection) against earlier type B.1 (D614G) emerges, and here also for delta, when compared to convalescents with one or two doses.

DOI: 10.1101/2021.07.01.450676.

 

[2hats]

Both studies underline why designers of next generation vaccines should consider a border range of virus proteins (eg RTC, nucleocapsid) and not just focus on spike.

Apropos of this, an animal study (University of Minnesota) of a human adenovirus viral vector vaccine expressing SARS-CoV-2 nucleocapsid (N) protein (Ad5-N). A viral challenge of vaccinated mice was associated with rapid N-specific T cell recall responses in the respiratory mucosa. Lung viral loads were significantly lower in vaccinees exposed to both WA early type and alpha/B.1.1.7.

This study supports the rationale for including additional SARS-CoV-2 antigens into future vaccine candidates, to broaden epitope diversity, increase protection and lessen escape in the face of a wider range of both existing and new variants.
DOI: 10.4049/jimmunol.2100421.

 

[2hats]

A preprint of a longitudinal analysis over 1.8 million SARS-CoV-2 genomes from 183 countries/territories to capture vaccination-associated viral evolutionary patterns. It might present the first evidence that vaccination is restricting the evolutionary and antigenic escape pathways accessible to SARS-CoV-2.

At national level, diversity of the SARS-CoV-2 lineages appeared to be declining with increased rate of mass vaccination.

T cell epitopes were found to be significantly less mutated than B cell epitopes. This suggests antibody-interfacing antigenic sites are under a stronger selection pressure compared to the T cell binding epitopes: breakthrough and escape mutations have a higher likelihood of occurring in neutralising antibody-binding residues on the spike, whilst T cell responses are better conserved across VOCs.

Additionally, in vaccine breakthrough patients, SARS-CoV-2 exhibited significantly lower diversity in known B cell epitopes compared to unvaccinated COVID-19 patients, and they also displayed fewer COVID-associated complications and pre-existing conditions relative to unvaccinated patients.
DOI: 10.1101/2021.07.01.21259833.