Issue #48: COVID-19 vaccines and influenza vaccines: Part 2 live attenuated vaccines

Written by Nobel Laureate Professor Peter Doherty

Last week (#47), I pointed out that our annual influenza (flu) shot is a cocktail of three or four different vaccines against two influenza A (H1N1 and H3N2) and one or two influenza B viruses (#46), while the current COVID-19 vaccines are directed at just one variant of the SARS-CoV-2 spike protein. That discussion (#47) ended with mention of the live-attenuated, whole virus flu vaccines that undergo limited replication in the upper respiratory tract after being sprayed up each nostril. Comparable vaccines are in development for SARS-CoV-2 but, because of the possibility of back-mutation (reversion) to give a virulent and fully infectious virus, any such product will need to be evaluated with great caution.

In days gone by, these low pathogenicity (low-path) vaccine variants were generated via serial passage in tissue culture (Sabin poliovirus vaccine, measles vaccine) or in animal species (yellow fever vaccine), a process that led to ‘adaptive’ mutational change and the emergence of less infectious (for children and adults) variants. Today, with our intimate (though still advancing) understanding of the molecular replication strategies used by any given virus, they would likely be made by directly changing the nucleic acid bases (#6) in genes coding for one or more virus proteins essential for optimal virus growth.

Of the various live-attenuated virus vaccines – we can add the mumps, rubella, rotavirus and chicken pox/shingles vaccines to the list – the oldest in widespread use is the Sabin oral poliovirus vaccine (OPV), the one that’s given on a sugar cube. As illustrated so beautifully in Australian filmmaker Sonya Pemberton’s wonderful documentary on vaccination (Jabbed, it aired on SBS and the US PBS network), OPV must not be given to children suffering from genetic immunocompromise – for example X-linked immunodeficiency disease in boys – as it can potentially cause poliomyelitis. And, in the global campaign to eradicate poliomyelitis (massively sponsored by Rotary), the end stages of elimination in any region always use the killed Salk polio vaccine to avoid the possibility that an OPV revertant can start to circulate in the population, a well-known phenomenon.

So why are live-attenuated vaccines attractive to manufacturers and public health specialists? Their first advantage is that, because they multiply up in us to give a lot of antigen (#18, #19), a very low dose of virus can be used in the vaccine. Providing there is a suitable cold chain, which requires only the temperatures we would normally associate with a domestic refrigerator or refrigerated truck, these are very economical vaccines. And there are live-attenuated coronavirus vaccines in use, but they’re for chickens!

The avian infectious bronchitis virus (IBV) coronavirus causes massive economic loss in chicken production facilities. The live-attenuated IBV vaccines are extremely inexpensive – a priority for use in this industry – and are easily administered in drinking water or aerosolised over a whole batch of week-old chicks. Reversion to virulence resulting from back mutation or reassortment (#46) between naturally circulating ‘wild type’ (the term used in genetics for an original strain of anything) and vaccine variants can occur. There are a number of avian gamma-coronaviruses like IBV that, as with the alpha and beta (including SARS-CoV-2) types that have so far infected us, probably originated from bats.

Of course, live virus vaccines mimic natural infection with ‘wild-type’ variants in that they potentially prime the individual to respond to all immunogenic virus proteins and to the various peptide/major histocompatibility complex combinations (#29, #33) that target (#34) the CD8+ killer (pMHCI) and CD4+ helper (pMHCII) T cells (#22, #42). With SARS-CoV-2, our efforts to develop protective antibodies (Igs, #21, #22) are directed almost exclusively against the spike protein RBD (receptor binding domain for ACE2, #19, #20), the primary component of the vaccine. With influenza, on the other hand, though current vaccines target the surface hemagglutinin (H, #46), some protective immunity can also be directed at the neuraminidase (N) molecule which is, of course, also made by the live-attenuated vaccines. There is also another influenza protein of interest re immunisation, though I’ll leave the discussion of that until we get to a consideration of possible cross-reactive vaccines.

So, should we be directing our COVID-19 research more towards the production of live-attenuated vaccines? Given the extraordinary success with both the mRNA and the adenovirus-vectored vaccines, the only scenario where I can imagine that going forward is with manufacturers who are focused primarily on providing masses of low-cost vaccine to developing countries. And the other issue is that our understanding of protective immunity in COVID-19 is still limited. There is no doubt that neutralising Igs specific for the spike RBD are ‘good’ but, while we have not seen this with the current SARS-CoV-2 vaccines (#43, #44, #45), there’s also the potential that exposure to a live-attenuated whole virus vaccine might trigger the production of ‘bad’ antibodies, like ‘enhancing antibodies’ that can increase the severity of infection (#47). Any such problems would, though, seem more likely to emerge after the high antigen dose resulting from natural infection with fully virulent virus.