Recombinant vector vaccines and within-host evolution

James Bull; Scott L. Nuismer; Rustom Antia

Revertant Vaccine (Antigen threshold) Figure 1 : Independent growth of vaccine (blue) and revertant (green). The revertant virus has the superior growth rate, but in the absence of interference between the two, vaccine growth is unimpeded and immunity is triggered. growth and thereby suppresses antigen production. 103 The challenges are thus to understand (i) when and how much vaccine evolution occurs; (ii) whether and to 104 what extent that evolution affects the abundance of vaccine virus; and (iii) the extent to which change in the 105 vaccine abundance affects the generation of adaptive immunity against the antigen. The arguments presented 106 above are qualitative and only superficially identify the scope of the problem. Quantitative understanding 107 ultimately rests on analysis of mathematical models. However, as the models have many interacting processes 108 -minimally innate immunity, adaptive immunity and intrinsic growth differences between vaccine versus inferiority. Yet even if vaccine selective 'neutrality' turns out to be fleeting, merely a mistaken impression 119 from short-term observations, we will find that the phenomenon of short-term stability mirrors a solution to 120 minimize vaccine evolution within the host. infections [26] [27] [28] [29] . The relative role of each mechanism in clearing infections is the basis of ongoing discussion, 145 but it is widely accepted that the roles differ among infections by different viruses and that each mechanism 146 is potentially important for some viruses. Adaptive immunity. 165 Adaptive immunity can be induced by the wild-type vector and the vaccine virus. Adaptive immune responses 166 specific to antigens expressed by the wild-type vector will presumably affect the vaccine and revertant equally 167 -because the vaccine encodes a complete vector genome, and the revertant is also a complete vector. As with 168 the preceding pair of mechanisms, adaptive immunity common to both revertant and vaccine will operate so 169 that revertant abundance will depress vaccine. Adaptive immunity to the vaccine antigen will be considered 170 shortly. The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/545087 doi: bioRxiv preprint one mechanism may take precedence over the others, simply because it is activated earlier or enforces a lower 173 limit on viral density than the others. However, there are different stages or degrees of vaccine suppression, 174 so an early mechanism may act to control the infection without clearing it, and another mechanism may 175 act later to clear. Because of the delay in developing an adaptive response, viral suppression by adaptive 176 immunity typically occurs later than effects of innate immunity or resource limitation and so might seem 177 to be unimportant in vaccine evolution. Yet adaptive immunity may be important in clearing the vaccine 178 following control by other mechanisms, in which case it could have an important role in vaccine evolution. The preceding paragraphs omitted adaptive immunity to the antigen. By its very nature, adaptive immunity 182 suppresses vaccine growth. But adaptive immunity to the antigen is specific to the vaccine and is thus 183 another reason -besides intrinsic fitness effects -that the vaccine may have lower fitness than revertant.