21 May 2021 Episode 141 Heterologous prime-boost; new African variants and pan-Corona vaccines

Dear colleagues,

The highlights of this episode:

• Heterologous prime boost is already applied in the real world of SARS-CoV-2 vaccination, but good controlled data are still awaited.
• A focus on new variants in Africa (B. 1.620; B.1.525; A23 and C1.1). They provide further evidence of viral escape by convergent evolution and there are clear bilateral links with Europe.
• Emerging data of new zoonotic Coronaviruses from dogs and pigs in human
• Various new strategies to develop broader or even pan-Corona vaccines, targeting human and animal coronaviruses and based on B and T cell immune responses.

1. Heterologous prime-boost: with Astra-Zeneca prime and Pfizer boost is being applied already in various European countries (Germany, France, Sweden, Norway, and Denmark), because of safety concerns with AZ.  After the first two deadly incidents, probably also soon in Belgium?

Heterologous prime-boost regimens (usually DNA prime and vector boost) have a good track record in experimental vaccinology, but in this case, most real world experiments are uncontrolled. Here are two emerging more controlled trials:   

Ep 141-1 Ellen Callaway in Nature reports on an unpublished Spanish study, comparing prime AZ alone with prime AZ + Pfizer boost.  Not surprisingly, the antibody response in the prime-boost group is higher, but this is not a fair comparison….

Ep 141-2 Shaw in Lancet discusses the first results of the Com-Cov, which compares various prime-boost regimens in systematic way. Not surprisingly “systemic reactogenicity” after heterologous prime-boost is higher as compared to homologous schedules, but no severe side effects were noted.  More important immunogenicity data are yet to be unveiled….

2. New SARS-COV-2 VOI/VOC and other emerging Coronaviruses

Ep 141-3: Meredith Wadman describes the blind spots in sequencing and briefly discusses about the new B.1.620 variant from Cameroon and CAR.

Ep 141-4: According to Dudas and Baele, this Central African VOC B.1.620 is likely to partly escape antibody-mediated immunity (probably similar to South-African and Brazilian VOC).  B.1.260 carries P26S, HV69/70D, V126A, Y144D, LLA241/243D and H245Y in the N-terminal domain of the Spike and, importantly, also the S477N and E484K in the RBD. 

As a reminder the spike mutations in the “South-African variant” B.1.315: D80A
D215G:K417N; E484K; N501Y and A701V.  The same E484K is also present in the Brazilian P1 and P2 and a related E484Q mutation is found in the Indian B.1.617.
 

Fig 2 p.7 and 3 p.8 show the relation between the various B.1.620 found:

• There is a clear importation from Cameroon into Belgium and France
• It has spread in various other European countries (Lithuana, Belgium, France, Germany and Catalonia).

The authors conclude Our work highlights that global inequalities, as far as infectious disease monitoring is concerned, have tangible impacts around the world and that until the SARS-CoV-2 pandemic is brought to heel everywhere, nowhere is safe for long.

Ep 141-5  takes the African perspective, looking at 8746 genomes from 33 African countries and showing that the early epidemic started with importations from Europe and that later, after travel restrictions from Europa, the viruses spread within and between African countries, with emergence of variants of concern, including of course the South-African B.1.315, but also 3 other VOC

• B.1.525, characterized by six substitutions in the spike protein (Q52R, A67V, E484K, D614G, O677H and F888L), and two deletions in the N-terminal domain (HV69-70Δ and Y144Δ), the latter in common with B.1.620  .  It originated in Nigeria and spreads in West-Africa
• A.23, characterized by three spike mutations (F157L, V367F and Q613H), first detected in a Ugandan prison. Later completed with other spike mutations R102I, L141F, E484K, P681R.  The latter mutation in the furin cleavage site also occurs in the “Indian variant” (B.1.617) and a similar P681H in the “British variant (B.1.117).
• C1.1 emerged in Johannesburg and is defined by the spike mutations S477N, A688S, M1237I and also contains the Q52R and A67V mutations similar to B.1.525.  Note that the S477N is common with the New York variant B.1526.

Clearly, there is strong evidence of epidemiological linkage between Europe and Africa, with 64% of detectable viral imports into Africa originating in Europe and 41% of detectable viral exports from Africa landing in Europe

Some level of convergent evolution in mutations is also evident: several crucial mutations have arisen around the same time, independently from each other in different parts of the world.

Ep 141.6: Vlasova et al describe in CID the isolation and genetic characterization of a novel canine-feline recombinant alphacoronavirus from a human pneumonia patient in Malaysia.  It is named CCoV-HuPn-2018 and contains a potentially crucial deletion in the N protein, which may have helped the crossing of species.  

Ep 141-7: Lednicky et al report in medRxiv on porcine delta-coronavirus infections among three children in Haiti with feverish abdominal pain and cough.  From genetic analysis the authors conclude that these infections are the result of at least two independent zoonoses of distinct viral lineages that acquired the same mutational signature in the nsp15 and the spike glycoprotein genes by convergent evolution to accommodate for the putative coronavirus cellular receptor aminopeptidase N. (See Luan Curr Med Chem 2007;14(6):639-47.  doi: 10.2174/092986707780059571.)

Ep 141-8 A and B: the associated press communications.

3. Perspectives on broad-spectrum Coronavirus vaccines

Ep 141-9: Walls in medRxiv is testing a multimeric receptor binding domain (RBD) SARS-CoV-2 protein vaccine in mice and macaques and shows that it elicits potent neutralizing antibodies in non-human primates (NHP) with some expected decreased activity against the E484K mutants and South-African variant.  Vaccinated mice were protected against a challenge with a mouse adapted  SARS-CoV-2. The antibodies, induced in NHP cross-react with SARS-CoV, Pangolin and Bat sarbecoviruses as well (but no neut is shown).

Ep 141-10 : a similar exercise with prefusion spike and RBD protein ferritin nanoparticles elicits very high neutralizing titers in mice, with cross-neutralization of SARS-CoV-1.  Passive transfer of the elicited IgG could protect human ACE-2 transgenic mice against an otherwise lethal challenge with SARS-CoV-2.    

Ep 141-11: In 141-11 A  Hauser et al present a strategy of RBD homotrimer protein design of three different Sarbecoviruses: SARS, SARS-CoV-2 and WIV1, the latter is a bat virus that they predicted in 2016 as potential zoonotic threat to humans ( See Ep 141-11 B!!!!).  In a mouse immunogenicity experiment, they show that immunization with a cocktail of these three different RBD homotrimers elicits cross-neutralizing antibodies against all three viruses in vitro at very decent titers (> 1000).  Remarkably also, these cross-neutralizing Ab are focused towards epitopes outside the ACE-2 binding pocket !!!

Ep 141-12: Prakash et al propose an analytic approach to identify highly conserved epitopes for B and T cells amongst several human and animal coronaviruses, with the aim to develop a “pre-emptive pan-corona vaccine”.  The approach includes testing which of the pan-corona conserved epitopes elicit CD4+ and CD8+ T cell responses in transgenic mice, which express ‘human” HLA- A2 and DR1 MHC and which epitopes are recognized by T c ells from convalescent SARS-COV-2 and naïve humans. Similarly, potential B cell epitopes are checked for binding to IgG of recovered SARS-CoV-2 patients and for eliciting antibody responses in B6 mice. The main findings are nicely summarized figure 8 p. 14.

There are clear limitations, as the transgenic mice express only 2 MHC molecules, which are present in 30 % (A2 for CD8 T cells) or 10 % (DR1 for CD4 T cells) of humans.  Moreover, it is not sure that the antibody response in B6 mice will be predictive for humans.  Finally, this multi-epitope vaccine cannot be used as such (peptides are poorly immunogenic), but will have to be developed in an mRNA or other format.  Nevertheless this is a nice start.

Ep 141-13:   A similar exercise by Minchao Li et al is focusing on the known human viruses and on CD8 T cell epitopes, but takes the huma HLA class 1 variability into account. This paper is limited to the bio-informatics approach and will need to be tested with human and animal samples.  

Best wishes

Guido