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Vaccine-related papers

Mix-and-match vaccination studies provide encouraging results, but further research necessary

Two recent papers provide support for mix-and-match vaccination, though questions still remain.

A German study looked at immune responses after an initial AstraZeneca/Oxford shot followed either by another dose of the same vaccine (in 32 participants) or by the Pfizer/BioNTech vaccine (55 participants). Some antibodies increased 11.5-fold after the Pfizer/BioNTech dose, compared with 2.9-fold for a second AstraZeneca dose. T cell and neutralising antibodies were also boosted substantially more after the Pfizer/BioNTech shot. The mixed vaccination also showed better neutralisation activity against the Alpha, Beta and Gamma variants.

The study was opportunistic, taking advantage of a pause in AstraZeneca/Oxford vaccinations following concerns about blood clots. Comparisons of immune responses with an initial Pfizer/BioNTech shot followed by the AstraZeneca/Oxford have not yet been undertaken. The paper was published in Nature Medicine.

A similar result was seen in a Swedish study where a Moderna vaccine dose was given after an initial AstraZeneca/Oxford shot. Higher levels of antibody binding and neutralising activity were seen for the mixed vaccination, and neutralising activity was also stronger against the Beta variant. This study also involved only small numbers of participants. The paper was published in the New England Journal of Medicine.

A commentary in Nature summarises the results from such mix-and-match studies. It highlights that further research on the safety of the strategy is required.

Benefits of vaccination within households

Further evidence supports vaccinations indirectly reducing the risk of infection in unvaccinated household members. In this Finnish study the indirect effectiveness for unvaccinated adults was calculated to be 8.7% two weeks after the first dose, increasing to 42.9% at 10 weeks (although the confidence intervals are broad). For under 18 year olds the protective effect was smaller and less precise due to fewer young people being tested.  These results are based on vaccinations with the Pfizer/BioNTech and Moderna vaccines. The paper has not yet been peer reviewed.

Israel sees decline in vaccine efficacy

Last week the Israeli Ministry of Health announced that Pfizer/BioNTech vaccine efficacy had declined markedly since June. This coincided with the spread of the Delta variant, though a causal relationship hasn’t yet been determined. Vaccine effectiveness in preventing infection and symptomatic illness has fallen to 64% for both, although effectiveness at preventing serious illness remains high at 93%.

Third Pfizer/BioNTech shot being tested

Pfizer and BioNTech are testing a third dose of their vaccine. They report in a press release that it results in five to 10 times higher neutralisation activity against the Beta variant, compared to the two doses, when given six months after the second dose. A paper on the results has not yet been released.  

Risk vs benefit of mRNA vaccination

While males under 30 have a higher risk of developing myocarditis after receiving an mRNA vaccine, this is outweighed by the benefits of vaccination. A US analysis calculated that for 18-29 year old males, vaccination can prevent 11,000 Covid-19 cases and 560 hospitalisation per million second doses, compared to under 50 expected cases of myocarditis. For older males (and females) the benefits are even greater. The paper was published in Morbidity and Mortality Weekly Report.

Potential correlate of protection from vaccination

Two separate analyses indicate that neutralising activity stimulated by vaccines provides a good correlate of protection. Concentrations of binding antibodies also correlate with vaccine efficacy. One of the papers was published in Vaccine, and the other in Nature Medicine.

A News and Views article in Nature Medicine discusses the significance of the two papers. It also notes the risk of using such correlates of protection. As the term implies they are correlations, not necessarily a causation of protection. The article suggests that further study of infections following vaccination will provide help identify what are reliable indicators of vaccine effectiveness.

Vaccinations affecting viral diversity

Diversity of viral lineages appears to be decreasing in countries where mass vaccination is well advanced. Viral genomes from 23 vaccinated people who became infected also showed lower levels of diversity that the diversity found in 30 unvaccinated infected people. The study also found that sites in the genome that are recognised by T cells are less diverse than those to which antibodies bind, so vaccines that include T cell binding sites may provide more durable protection. The paper has not yet been peer reviewed.

Inhalable vaccine in development

An inhalable Covid-19 vaccine, based on a parainfluenza virus, prevented infections in a mouse strain and ferrets. Only four to six animals were used for each test. The paper was published in Science Advances.

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Non-vaccine-related papers

Higher viral loads seen in a Delta variant outbreak

People infected with the Delta variant in China were found to carry higher viral loads than seen earlier in the pandemic. All 167 infections associated with the first Delta variant outbreak in mainland China were traced back to the index case. The index case had a viral load about 1,000 times higher than seen for loads seen earlier in the pandemic for other variants. More of those subsequently infected also had lower Ct values in PCR tests, indicating higher viral loads, compared to infections from an earlier strain. The paper has not yet been peer reviewed.

Delta variant more infective in cell tests

The Delta variant has an increased ability to infect and fuse cultured lung cells. This probably contributes to its greater transmissibility, and possibly higher pathogenicity. One monoclonal antibody was ineffective in inhibiting the variant, but the expectation is that other monoclonal antibodies will be effective. The paper has not yet been peer reviewed.

Potential protection due to previous human coronavirus infections

Development of mild Covid-19 might be related to T cells from previous human coronavirus infections. CD8+ T memory cells that recognise conserved regions in coronaviruses were higher in patients who had mild Covid-19 (13 people), compared with those with severe cases (11 patients). The cross-reactivity of these T cells may therefore be associated with protection. The paper was published in Science Immunology.

Human genome associations with infection and Covid-19 severity

An analysis of earlier studies of the genomes of nearly 50,000 Covid-19 patients in 19 countries found genetic links to susceptibility. In comparison with 2 million control genomes the study identified 13 loci associated with infection or severe Covid-19. Four of these appear linked to susceptibility to infection, and nine to disease severity. While some of the genomic sites are already associated with lung or autoimmune diseases, other loci are novel.

Due to challenges in comparing different studies, further research is needed to establish whether some or all of these loci do increase susceptibility to Covid-19. The paper was published in Nature. A News & Views article summarises the key findings of this paper.

Sustained immune responses found in cases of severe Covid-19

While it’s previously been reported that severe Covid-19 may in part be due to delayed or unbalanced immune responses, a recent study found that broad and sustained immunoreactivity against SARS-CoV-2 was associated with  COVID-19 severity. High titers of Spike-binding and virus-neutralizing antibodies were associated with more severe cases, although there was considerable variability in responses.

A group of “High responders” maintained high levels of neutralisation activity over seven months. The study involved only recovered Covid-19 patients. The paper was published in PLOS Medicine.

Long lasting neutralising antibodies

Antibodies that neutralise the spike protein are longer lasting than those targeting the viral nucleoprotein. Repeated serum samples were taken from 349 infected healthcare workers (who did not require hospitalisation) for up to 200 days. Over 95% had detectable antibodies during this time. Antibodies against the nucleoprotein had an expected half life of 60 days, whereas the spike protein antibodies were predicted to last around 465 days in 95% of infected people.  Antibodies against the receptor binding domain were also long lasting. The paper was published in Clinical Infectious Diseases.

Ultrapotent antibodies

Four antibodies have been identified which have strong neutralising activity against 23 variants, including the variants of concern. Two of the antibodies are deemed “ultrapotent”, being effective at very low doses. Treatments that use pairs of these antibodies may help control spread of the variants, and reduce the risks of new ones emerging. The paper was published in Science.  

Positive and negative selection acting on the SARS-CoV-2 genome

Analysis of more than 300,000 SARS-CoV-2 genomes identified sites of positive selection. Sequenced genomes collected up until January 2021 showed waves genetic and regional stasis and diversification. While most sites in the viral genome appear subject to negative (or purifying selection), with limited mutations, the receptor binding domain of the spike protein and a region of the nucleocapsid protein appear to show sites undergoing positive selection that may aid immune evasion. The paper was published in the Proceedings of the National Academy of Sciences.

Hospitalisation risks may increase after Covid-19

People who have recovered from severe Covid-19 may be at an increased subsequent risk of hospitalisation for non-Covid-related conditions. This is based on an analysis of over 10,000 peoples’ health records six months after infection (just over 300 of whom had been infected). Compared to people who had had mild Covid-19 the hazard ratio was 2.20 higher for those with severe Covid-19, and 2.24 higher when compared to patients who had not been infected. The paper is to be published in the Journal of the American Board of Family Medicine.

Another rapid, cheap and accurate test in development

A rapid low-cost sensor shows very high level sensitivity, specificity and accuracy for SARS-CoV-2 detection. It tests saliva or nasopharyngeal swabs, and results can be available in under seven minutes, at a cost of US$1.50 per test. The paper was published in the Proceedings of the National Academy of Sciences.

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